Gender
differences in myocardial structure, function and metabolism
Dr. A.S. Clanachan1, Dr. H.
Fraser2
1Department of Pharmacology, Cardiovascular
Research Group,
Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta
T6G 2H7, Canada, and 2Division of Cardiology, Johns Hopkins University,
Baltimore, MD, USA
Gender differences in cardiac function and metabolism
are attracting considerable interest, particularly in relation
to mechanisms responsible for the relative resistance of premenopausal
females to ischemic heart disease. The delay in onset of cardiovascular
disease in women before the menopausal years suggests that
female sex hormones might possess cardioprotective properties.
However, it is still unclear whether cardioprotection is due
to circulating estrogen or to an inherent ability of female
hearts to resist damage. Nevertheless, the potential benefit
of estrogen has prompted its widespread clinical use and has
stimulated numerous experimental investigations into the putative
beneficial actions of estrogen replacement therapy. There is
considerable evidence that physiologic concentrations of estrogen
elicit a number of effects on function and metabolism that
may contribute to the ability of the female heart to resist
ischemic damage.
Introduction
Examination of the incidence of a broad spectrum of cardiovascular diseases
has indicated that female gender is a protective factor.[1,2]
Moreover, cardiovascular mortality rates are lower in premenopausal women than
in males of equivalent age. The lack of any specific behavioral effect to account
for such cardioprotection and the similarity in cardiovascular events between
older men and menopausal women suggest that female sex hormones might possess
cardioprotective properties.[3] Gender-dependent protection
is also observed in patients with heart failure. However, it is still unclear
if the resistance of the female heart is due to estrogen or to an inherent
ability of the female heart to resist injury.
Cardiac structure
Premenopausal women have smaller hearts, but relative to total body mass, there
is no difference when compared with men.[4] Left ventricular
(LV) wall thickness, but not LV wall mass, increases after menopause,[5] whereas
increases in LV mass during hormone replacement therapy (HRT) have been noted
in some[6] but not all studies.[7] Cardiac
fibroblasts, which contribute to structural remodeling associated with myocardial
infarction and reperfusion injury, comprise ~60% of the total heart cells.
Cardiac fibroblasts possess estrogen receptors, and both increases[8] and
decreases[9] in fibroblast proliferation have been reported
with estrogen replacement therapy (ERT). The survival advantage in women
may also be related to gender-related differences in the degree of myocardial
hypertrophy and a preserved systolic function.[10]
Cardiac dysfunction
Impairment of cardiac function may arise as a consequence of the loss of cardiomyocytes
by necrosis and/or apoptosis. There are marked differences in the rates of
necrosis and apoptosis between male and female hearts, particularly following
the onset of cardiac failure.[11] Gender differences are
also manifest during acute coronary occlusion when females have a greater vagal
activation and fewer cardiac dysrhythmias.[12] Thus, while
it is conceivable that the female heart resists injury by some, as yet unidentified,
inherent property, considerable attention has focused on the cardioprotective
properties of estrogen.
ERT is considered to reduce the risk of cardiovascular disease in menopausal
females,[1,3] although recent evidence from a large (n = 2763)
randomized trial indicated that HRT consisting of a combination of conjugated
estrogens and medroxyprogesterone exerts no significant beneficial actions.[13] While
the cardioprotective efficacy of estrogen per se was not assessed, reports
of improved cholesterol profiles,[14] decreased insulin resistance
and enhanced glucose tolerance[15] by ERT provide evidence
that estrogen may offer protection against coronary heart disease. Moreover,
experimental data that demonstrate a reduction in myocardial necrosis after
ischemia and reperfusion by chronic 17b-estradiol[16] and
an improved recovery of post-ischemic contractile function in hearts perfused
ex vivo[17,18] suggest that mechanisms occurring directly
in the heart also contribute to estrogen-induced cardioprotection. While most
experimental models of estrogen-induced cardioprotection require chronic therapy,
rapid non-genomic actions of estrogen may also be involved.
Indirect protective mechanisms
of estrogen
Indirect (non-cardiac) mechanisms proposed for the cardioprotective actions
of estrogen include reduced responses to vascular injury arising, in part,
from alterations in lipid metabolism that improve the ratio of HDL to LDL.
Indeed, this has been considered the principal mechanism of protection.[19] Estrogen
also inhibits LDL oxidation and so limits atherosclerotic plaque formation.[20] Moreover,
estrogen may exert an additional protective action on the circulation by virtue
of an antioxidant activity.[21] Similar reduction in cardiovascular
risk factors has been observed with raloxifene, a selective estrogen receptor
modulator.[22]
Vasodilator properties of estrogen have been described, including increased
blood flow in the carotid and coronary arteries.[23,24] While
inhibition of L-type Ca2+ channels occurs with 17b-estradiol concentrations
much higher than those associated with ERT,[23] there is
considerable evidence for enhanced nitric oxide (NO) biosignaling by clinical
concentrations of estrogen[25] that can exert an array of
beneficial effects on blood-borne cellular elements (inhibition of platelet
aggregation and neutrophil adhesion) as well as vascular smooth muscle (vasorelaxation
and inhibition of proliferation). Key findings include an estrogen-induced
increase in the expression and activity of NO synthases that facilitate endogenous
NO production.[26] Female vascular endothelium has an enhanced
capacity to produce NO and reduce smooth muscle tone,[27] and
there is a similar enhanced endothelial-dependent (NO-mediated) relaxation
in 17b-estradiol-treated male rats.[27] Finally, estrogen-induced
release of vascular endothelium growth factor may stimulate coronary angiogenesis.[28]
Figure 1. Cardioprotective mechanisms of estrogen
Direct protective mechanisms of estrogen
A direct cardioprotective effect of estrogen is also demonstrable. While enhanced
NO biosignaling in the vasculature has been implicated in many of the cardiovascular
changes arising from estrogen, several cell types in the myocardium, including
endothelial cells[29] and cardiomyocytes,[30] possess
the various isoforms of NO synthase and can generate endogenous NO that may
benefit cardiac function. Estrogen upregulates NO synthase[25,26,31] in
cardiomyocytes, and a recent study that discovered enhanced myocardial NO biosignaling
(NO synthase activity and cGMP content) in hearts from estrogen-treated rats
provides strong evidence for a role of NO in the direct cardioprotective actions
of 17b-estradiol.[32]
Myocardial metabolism
Myocardial energy is generated mainly from the oxidation of fatty acids and
carbohydrates. Although the beta-oxidation of fatty acids is the more important
source of ATP production, glucose metabolism, particularly the relative rate
of glycolysis and glucose oxidation, is an important consideration during periods
of sympathetic activation or post-ischemic reperfusion. The rate of glycolysis
greatly exceeds that of glucose oxidation, a condition that leads to considerable
proton production and intracellular acidosis. Accumulation of Na+ (via the
Na+-H+ exchanger) and Ca2+ overload (via the Na+-Ca2+ exchanger) impair recovery
of mechanical function and myocardial efficiency upon reperfusion.[33] Overexpression
of the Na+-Ca2+ exchanger in male, but not in female, animals worsens recovery
of post-ischemic function, presumably by promoting greater Ca2+ overload. Interestingly,
bilateral ovariectomy prevents this gender difference and suggests that estrogen
may protect by mechanisms that ultimately affect Ca2+ overload.[34]
No direct examinations of gender differences in overall myocardial energy substrate
metabolism are available, but estrogen-induced regulation of glucose metabolism
is demonstrable. Estrogen increases glycogen deposition in heart[35] and
improves exercise tolerance and prevents depletion of myocardial glycogen.[36] Estrogen
signaling pathways have also been implicated in the translational control of
enzymes in fatty acid and glucose metabolism by the nuclear receptor, peroxisome
proliferator-activated receptor-alpha.[37]
Direct assessment of rates of myocardial glycolysis and glucose oxidation in
hearts removed from rats treated chronically with 17b-estradiol revealed an
acceleration of glucose oxidation both during aerobic perfusion and during
post-ischemic reperfusion.[18] These data, in combination
with the well-documented benefits elicited by the optimization of myocardial
glucose metabolism,[38,39] suggest that changes in glucose metabolism arising
from chronic 17b-estradiol treatment may indeed contribute to the direct cardioprotective
efficacy of estrogen.
Conclusion
There are important gender-based differences that affect cardiovascular function
and resistance to injury, including direct estrogen-mediated changes in cardiac
function and metabolism, as well as indirect factors that alter the coronary
and systemic vasculature and the generation of atherosclerosis. Ongoing clinical
and basic research aims to identify more carefully the mechanisms underlying
such gender-related differences and to exploit pharmacologically these effects
so that the full cardioprotective efficacy of estrogen and selective estrogen
receptor modulators can be realized for both male and female patients.
REFERENCES
-
Estrogen replacement therapy and coronary
heart disease: a quantitative assessment of the epidemiologic
evidence.
Stampfer MJ, Colditz GA.
Channing Laboratory, Boston, MA 02115.
Considerable epidemiological evidence has accumulated regarding the effect
of postmenopausal estrogens on coronary heart disease risk. Five hospital-based
case-control studies yielded inconsistent but generally null results; however,
these are difficult to interpret due to the problems in selecting appropriate
controls. Six population-based case-control studies found decreased relative
risks among estrogen users, though only 1 was statistically significant.
Three cross-sectional studies of women with or without stenosis on coronary
angiography each showed markedly less atherosclerosis among estrogen users.
Of 16 prospective studies, 15 found decreased relative risks, in most instances,
statistically significant. The Framingham study alone observed an elevated
risk, which was not statistically significant when angina was omitted. A
reanalysis of the data showed a nonsignificant protective effect among younger
women and a nonsignificant increase in risk among older women. Overall, the
bulk of the evidence strongly supports a protective effect of estrogens that
is unlikely to be explained by confounding factors. This benefit is consistent
with the effect of estrogens on lipoprotein subfractions (decreasing low-density
lipoprotein levels and elevating high-density lipoprotein levels). A quantitative
overview of all studies taken together yielded a relative risk of 0.56 (95%
confidence interval 0.50-0.61), and taking only the internally controlled
prospective and angiographic studies, the relative risk was 0.50 (95% confidence
interval 0.43-0.56).
Publication Types:
PMID: 1826173 [PubMed - indexed for MEDLINE]
-
Gender differences in survival in advanced
heart failure. Insights from the FIRST study.
Adams KF Jr, Sueta CA, Gheorghiade M, O'Connor CM, Schwartz
TA, Koch GG, Uretsky B, Swedberg K, McKenna W, Soler-Soler
J, Califf RM.
University of North Carolina at Chapel Hill, 27599-7075, USA. kfa@med.unc.edu
BACKGROUND: Previous natural history studies in broad populations of heart
failure patients have associated female gender with improved survival, particularly
in patients with a nonischemic etiology of ventricular dysfunction. This
study investigates whether a similar survival advantage for women would be
evident among patients with advanced heart failure. METHODS AND RESULTS:
The study analysis is based on the Flolan International Randomized Survival
Trial (FIRST) study which enrolled 471 patients (359 men and 112 women) who
had evidence of end-stage heart failure with marked symptoms (60% NYHA class
IV) and severe left ventricular dysfunction (left ventricular ejection fraction
18+/-4.9%). A Cox proportional-hazards model, adjusted for age, gender, 6-minute
walk, dobutamine use at randomization, mean pulmonary artery blood pressure,
and treatment assignment, showed a significant association between female
gender and better survival (relative risk of death for men versus women was
2.18, 95% CI 1.39 to 3.41; P<0.001). Although formal interaction testing
was negative (P=0.275), among patients with a nonischemic etiology of heart
failure, the relative risk of death for men versus women was 3.08 (95% CI
1.56 to 6.09, P=0.001), whereas among those with ischemic heart disease,
the relative risk of death for men versus women was 1.64 (95% CI 0.87 to
3.09, P=0.127). CONCLUSIONS: Women with advanced heart failure appear to
have better survival than men. Subgroup analysis suggests this finding is
strongest among patients with a nonischemic etiology of heart failure.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 10199877 [PubMed - indexed for MEDLINE]
-
Comment in:
Hormone therapy to prevent disease and prolong life
in postmenopausal women.
Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger
B, Ernster VL, Cummings SR.
University of California, Prevention Sciences Group, San Francisco 94105.
PURPOSE: To critically review the risks and benefits of hormone therapy for
asymptomatic postmenopausal women who are considering long-term hormone therapy
to prevent disease or to prolong life. DATA SOURCES: Review of the English-language
literature since 1970 on the effect of estrogen therapy and estrogen plus
progestin therapy on endometrial cancer, breast cancer, coronary heart disease,
osteoporosis, and stroke. We used standard meta-analytic statistical methods
to pool estimates from studies to determine summary relative risks for these
diseases in hormone users and modified lifetable methods to estimate changes
in lifetime probability and life expectancy due to use of hormone regimens.
RESULTS: There is evidence that estrogen therapy decreases risk for coronary
heart disease and for hip fracture, but long-term estrogen therapy increases
risk for endometrial cancer and may be associated with a small increase in
risk for breast cancer. The increase in endometrial cancer risk can probably
be avoided by adding a progestin to the estrogen regimen for women who have
a uterus, but the effects of combination hormones on risk for other diseases
has not been adequately studied. We present estimates for changes in lifetime
probabilities of disease and life expectancy due to hormone therapy in women
who have had a hysterectomy; with coronary heart disease; and at increased
risk for coronary heart disease, hip fracture, and breast cancer. CONCLUSIONS:
Hormone therapy should probably be recommended for women who have had a hysterectomy
and for those with coronary heart disease or at high risk for coronary heart
disease. For other women, the best course of action is unclear.
Publication Types:
PMID: 1443971 [PubMed - indexed for MEDLINE]
-
Relationship of cardiac size to maximal
oxygen uptake and body size in men and women.
Hutchinson PL, Cureton KJ, Outz H, Wilson G.
Springfield College, MA 01109.
It has been suggested in previous studies that the difference in endurance
performance between males and females is related to gender-specific differences
in cardiac function. Other studies have not equated males and females for
physical condition, and this may have contributed to the findings. The purpose
of this study was to determine the extent to which the difference in VO2max
in groups of similarly trained males and females was explained by gender
differences in cardiac size, fat-free weight (FFW) and hemoglobin concentration
[( Hb]). Measurements of VO2max, FFW, [Hb] and cardiac size (LVM) were made
on 19 males and 20 females comparable in age and cardiorespiratory capacity.
The difference between men and women in LVM accounted for 68.3% of the gender
difference in VO2max, and the combination of LVM and FFW accounted for 98.7%
of the gender-related difference in VO2max. It was concluded that the gender
difference in LVM accounts for a majority of the difference in VO2max in
males and females, with other aspects of body size accounting for nearly
all the remaining difference. The gender difference in heart size primarily
reflects the smaller overall dimensions of women.
PMID: 1917220 [PubMed - indexed for MEDLINE]
-
Comment in:
The effects of sublingual estradiol on left ventricular
function at rest and exercise in postmenopausal women: an echocardiographic
assessment.
Pines A, Fisman EZ, Drory Y, Shapira I, Averbuch M,
Eckstein N, Motro M, Levo Y, Ayalon D.
Department of Medicine, Tel-Aviv Elias Sourasky Medical Center, Israel.
OBJECTIVE: To evaluate the acute hemodynamic effects of 4 mg estradiol given
sublingually. DESIGN: Rest and exercise echocardiographies were performed
prior to estradiol administration. Then, another set of tests was done post-dose:
rest examination at 1 h post-dose, isometric exercise at 65 min post-dose,
and dynamic exercise at 100 min post-dose. RESULTS: The administration of
4 mg sublingual estradiol to 24 postmenopausal women (aged 48-58 years) was
followed 60 min post-dose by a surge in mean estradiol serum levels (1759
+/- 704 pg/ml). At rest a slight drop in systolic and diastolic blood pressure
was measured after estrogen ingestion: 132 +/- 24 mm Hg versus 127 +/- 21
mm Hg, p < 0.05; 83 +/- 11 mm Hg versus 78 +/- 10 mm Hg, p < 0.02.
There were no changes in resting heart rate, double product, or vascular
resistance. The left heart cavities became smaller: the left atrium diameter
decreased from 33.7 +/- 4 mm to 32.3 +/- 4 mm, p < 0.01; the end-systolic
diameter decreased from 24.9 +/- 3 mm to 23.6 +/- 4 mm, p < 0.01; the
end-diastolic diameter decreased from 44.5 +/- 4 mm to 42.7 +/- 4 mm, p < 0.01.
The peak aortic blood flow velocity fell from 120 +/- 19 cm/s to 116 +/-
22 cm/s (p < 0.05), and the flow velocity integral fell from 26.3 +/-
4 cm to 24.9 +/- 5 cm (p < 0.01); the cardiac output underwent a small
change, with borderline significance: 7 +/- 2 L/min versus 6.7 +/- 2 L/min,
p = 0.06. Only minor changes in the hemodynamic and echocardiographic parameters
were recorded after estrogen for both isometric and dynamic exercises. Analyses
were also made for two subgroups: 13 normotensive women were compared with
11 hypertensive women. The post-estrogen decreases in resting blood pressure
and in peak blood velocity were observed only in the hypertensive subjects,
whereas the changes in heart dimensions and in flow velocity integral were
the same in both subgroups. CONCLUSIONS: Sublingual estradiol was associated
with acute hemodynamic alterations mainly at rest but also after exercise.
PMID: 9689200 [PubMed - indexed for MEDLINE]
-
Effect of short-term hormone replacement
therapy on left ventricular mass and contractile function.
Sites CK, Tischler MD, Blackman JA, Niggel J, Fairbank
JT, O'Connell M, Ashikaga T.
Department of Obstetrics and Gynecology, University of Vermont College of
Medicine, Burlington 05405, USA.
OBJECTIVE: To determine the effect of hormone replacement therapy (HRT) on
cardiac structure and function and whether these changes are related to changes
in blood volume. DESIGN: Open-label pilot study. SETTING: Academic medical
center. PATIENT(S): Eighteen healthy postmenopausal women. INTERVENTION(S):
We administered medroxyprogesterone acetate orally, 5 mg/d for 2 months followed
by 2 months of oral sequential 17beta-estradiol, 1 mg/d plus medroxyprogesterone
acetate, 10 mg/d for the last 12 days of each month. MAIN OUTCOME MEASURE(S):
Cardiac output, stroke volume, heart rate, end diastolic volume, end systolic
volume, ejection fraction, and left ventricular mass were measured by echocardiography;
blood and plasma volumes were measured using 125I-albumin dilution. RESULT(S):
Cardiac output, stroke volume, left ventricular mass, end diastolic volume,
and ejection fraction increased by 12.8%, 11.7%, 9.4%, 7.2%, and 10.9%, respectively,
by 16 weeks. End systolic volume decreased, whereas heart rate was unaffected.
There was a significant increase in blood volume (5.2%) and plasma volume
(4.8%) from baseline during treatment, which could explain the increased
cardiac output but not the increased ejection fraction. CONCLUSION(S): Hormone
replacement therapy causes modest but significant increases in cardiac output,
ejection fraction, and left ventricular mass. These pilot data suggest a
direct myocardial effect of HRT that is preload independent.
Publication Types:
PMID: 9935130 [PubMed - indexed for MEDLINE]
-
-
Physiologic estradiol replacement therapy
and cardiac structure and function in normal postmenopausal
women: a randomized, double-blind, placebo-controlled,
crossover trial.
Snabes MC, Payne JP, Kopelen HA, Dunn JK, Young RL,
Zoghbi WA.
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston,
TX, USA.
OBJECTIVE: To assess the effect of estradiol (E2) replacement therapy on
cardiac structure and function in healthy postmenopausal women. METHODS:
We conducted a randomized, double-blind, placebo-controlled, crossover study
of 31 healthy postmenopausal female volunteer study subjects (55-65 years)
using 12 weeks of micronized E2 replacement therapy (2 mg/day). Echocardiography
and Doppler techniques were used to assess the cardiac effects of E2 at rest
and during graded bicycle ergometry. RESULTS: Crossover analysis demonstrated
no carryover effects of estrogen treatment (which increased serum E2 15-fold
to 37.6 pmol/L) on the cardiac characteristics measured. Estradiol treatment
did not affect measurements of systolic function, diastolic function, left
ventricular mass, or pulmonary artery pressure at rest or during bicycle
ergometry. Left ventricular end-diastolic volume at rest was slightly higher
with E2 treatment (P = .03). However, this change was not reflected by changes
in stroke volume, ejection fraction, or cardiac output. CONCLUSIONS: Estrogen
replacement therapy, which results in physiologic serum concentrations, does
not affect cardiac structure or function in normal postmenopausal women after
12 weeks of treatment.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 9052580 [PubMed - indexed for MEDLINE]
-
Estrogen enhances proliferative capacity
of cardiac fibroblasts by estrogen receptor- and mitogen-activated
protein kinase-dependent pathways.
Lee HW, Eghbali-Webb M.
Department of Anesthesiology, Yale University School of Medicine, New Haven,
CT 06510, USA.
The role of female hormones in the prevalence of cardiac diseases are recognized
but not fully explored. Proliferation of cardiac fibroblasts, the cellular
origin of the extracellular matrix proteins, growth factors and cytokines
in the heart, is an important underlying mechanism in the pathophysiological
remodeling of the myocardium. In this study, we have investigated the effect
of estrogen (17 beta-estradiol) on proliferative capacity of cardiac fibroblasts
obtained from adult female rat heart. DNA synthesis, as determined by incorporation
of 3H-thymidine into DNA, increased in estrogen-treated cells. In the presence
of tamoxifen, an anti-estrogen with high affinity for estrogen receptor.
17 beta-estradiol-induced stimulation of DNA synthesis was abolished. Alpha-estradiol,
a stereo-isomer which does not bind the estrogen receptor, did not change
DNA synthesis. In the presence of a synthetic inhibitor of MAP kinase pathway.
PD98059, estrogen failed to stimulate DNA synthesis. In-gel kinase assays
showed rapid and transient increased phosphorylation of MAP kinase substrate,
myelin basic protein (MBP), at 42 and 44 kDa by 17 beta-estradiol, which
was not observed in the presence of PD98059 and tamoxifen, not induced by
alpha-estradiol and persisted in the absence of protein kinase C. In vitro
kinase assay confirmed 17 beta-estradiol-induced activation of ERK1 and ERK2,
with predominant effect on ERK2 in cardiac fibroblasts. The results of immunofluorescent
light microscopy using anti-type alpha and beta estrogen receptor antibodies
showed the expression of estrogen receptor types alpha and beta in control
untreated cells, and indicated that type beta receptor is the predominant
type with both cytoplasmic and nuclear localization. 17 beta-estradiol treatment
of cardiac fibroblasts induced the translocation of receptor protein to the
nuclei. Together, these data provide evidence that cardiac fibroblasts are
cellular targets for direct effects of estrogen, and that this hormone enhances
proliferative capacity of cardiac fibroblasts via estrogen receptor- and
MAP kinase-dependent mechanisms. These data further suggest that estrogen,
by its growth-enhancing effects in cardiac fibroblasts, can regulate the
remodeling of the extracellular matrix and alter the microenvironment of
cardiac cells, and hence exert an impact on the integrity of myocardial function.
PMID: 9710804 [PubMed - indexed for MEDLINE]
9. Dubey RK, Gillespie DG, Jackson EK, Keller PJ. 17b-estradiol,
its metabolites, and progesterone inhibit cardiac fibroblast growth. Hypertension
1998; 31: 522–528.
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Comment in:
- Circulation. 1992 Oct;86(4):1336-8
Sex-associated differences in left ventricular function
in aortic stenosis of the elderly.
Carroll JD, Carroll EP, Feldman T, Ward DM, Lang RM,
McGaughey D, Karp RB.
Department of Internal Medicine, University of Chicago, IL 60637.
BACKGROUND. In aortic stenosis, the response of the left ventricle to pressure
overload varies from compensated hypertrophy to overt heart failure. The
determinants of left ventricular adaptation are poorly understood. METHODS
AND RESULTS. Left ventricular function was compared to assess the role of
sex in 34 women and 29 men 60 years or older with both hemodynamic and echocardiographic
data characteristic of severe aortic stenosis and no important coronary artery
disease. Despite a similar degree of left ventricular outflow obstruction
in women versus men (aortic valve area 0.54 +/- 0.20 versus 0.59 +/- 0.19
cm2, NS), the left ventricle of women had a greater fractional shortening
(37 +/- 12 versus 25 +/- 12%, p = 0.001), achieved a smaller end-systolic
chamber size (1.82 +/- 0.64 versus 2.17 +/- 0.65 cm/m2, p = 0.04), and generated
more pressure (210 +/- 35 versus 182 +/- 29 mm Hg, p = 0.001) with a greater
maximum positive dP/dt (2.153 +/- 794 versus 1,595 +/- 384 mm Hg/sec, p =
0.02). The men had a lower cardiac index (2.12 +/- 0.59 versus 2.49 +/- 0.63
l/min/m2, p = 0.02), higher mean pulmonary artery pressure (35 +/- 13 versus
27 +/- 10 mm Hg, p = 0.01), and shorter ejection period (340 +/- 40 versus
370 +/- 40 msec, p = 0.02). Women and men were equally symptomatic. Supernormal
left ventricular ejection performance was present in 41% of the women and
only 14% of the men (p = 0.002). This subgroup of women had a small, thick-walled
chamber (end-diastolic radius to thickness ratio, 1.58 +/- 0.52 versus 2.45
+/- 0.51 in control women, p = 0.01) with low end-systolic wall stress. Subnormal
ejection performance was present in 64% of the men and only 18% of the women
(p = 0.002). This subgroup of men had an increased chamber size and high
end-systolic wall stress compared with control men. Greater left ventricular
mass was present in men compared with women (211 +/- 55 versus 179 +/- 55
g/m2, p = 0.03). CONCLUSIONS. Sex is a factor in left ventricular adaptation
to valvular aortic stenosis in adults 60 years or older.
PMID: 1394918 [PubMed - indexed for MEDLINE]
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Comment in:
Myocyte death in the failing human heart is gender dependent.
Guerra S, Leri A, Wang X, Finato N, Di Loreto C, Beltrami
CA, Kajstura J, Anversa P.
Department of Medicine, New York Medical College, Valhalla, New York 10595,
USA.
Cardiovascular disease is delayed and less common in women than in men. Myocyte
death occurs in heart failure, but only apoptosis has been documented; the
role of myocyte necrosis is unknown. Therefore, we tested whether necrosis
is as important as apoptosis and whether myocyte death is lower in women
than in men with heart failure. Molecular probes were used to measure the
magnitude of myocyte necrosis and apoptosis in 7 women and 12 men undergoing
transplantation for cardiac failure. Myocyte necrosis was evaluated by detection
of DNA damage with blunt end fragments, whereas apoptosis was assessed by
the identification of double-strand DNA cleavage with single base or longer
3' overhangs. An identical analysis of these forms of cell death was performed
in control myocardium. Heart failure showed levels of myocyte necrosis 7-fold
greater than apoptosis in patients of both sexes. However, cell death was
2-fold higher in men than in women. Heart failure resulted in a 13-fold and
27-fold increase in necrosis in women and men, respectively. Apoptosis increased
35-fold in women and 85-fold in men. The differences in cell death between
women and men were confirmed by the electrophoretic pattern of DNA diffusion
and laddering of isolated myocytes. The lower degree of cell death in women
was associated with a longer duration of the myopathy, a later onset of cardiac
decompensation, and a longer interval between heart failure and transplantation.
In conclusion, myocyte necrosis and apoptosis affect the decompensated human
heart; each contributes to the evolution of cardiac failure. However, the
female heart is protected, at least in part, from necrotic and apoptotic
death signals.
PMID: 10532954 [PubMed - indexed for MEDLINE]
-
-
Gender difference in autonomic and hemodynamic
reactions to abrupt coronary occlusion.
Airaksinen KE, Ikaheimo MJ, Linnaluoto M, Tahvanainen
KU, Huikuri HV.
Department of Medicine, University of Oulu, Finland. kari.airaksinen@.oulu.fi
OBJECTIVES: We sought to determine whether there are gender-related differences
in autonomic and hemodynamic responses to abrupt coronary occlusion. BACKGROUND:
The risk of sudden death before hospital admission is higher in men with
an acute myocardial infarction. The reasons for this gender-related difference
are not well understood. Cardiovascular autonomic regulation modifies the
outcome of acute coronary events, and there are gender differences in the
autonomic regulation of heart rate (HR) in normal physiologic circumstances.
METHODS: We analyzed the changes in HR, HR variability and blood pressure
and the occurrence of ventricular ectopic beats during a 2-min coronary occlusion
in 140 men and 65 women referred for single-vessel coronary angioplasty.
The ranges of nonspecific responses were determined by analyzing a control
group of 19 patients with no ischemia during a 2-min balloon inflation in
a totally occluded coronary artery. RESULTS: Women more often had ST segment
changes (p < 0.01) and chest pain (p < 0.05) during the occlusion.
Significant bradycardia or increase in HR variability as a sign of vagal
activation occurred more often in women than in men (31% vs. 13%, p < 0.01
and 25% vs. 11%, p < 0.05, respectively). Coronary occlusion also more
often caused (28% vs. 11%, p < 0.01) a decrease in blood pressure in women.
The most pronounced female preponderance was in the incidence of Bezold-Jarisch-type
reaction (i.e., simultaneous bradycardia and decrease in blood pressure [16%
vs. 0.7%, p < 0.0001]). Logistic regression models developed to analyze
the significance of gender while controlling for baseline variables and signs
of ischemia identified female gender to be an independent predictor of bradycardic
reactions (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.4 to 7.7,
p < 0.01), hypotensive reactions (OR 2.6, 95% CI 1.1 to 6.0, p < 0.05)
and Bezold-Jarisch-type response (OR 22.2, 95% CI 2.5 to 200, p < 0.01).
Significance of female gender as a protector against early coronary occlusion-induced
ventricular ectopic beats emerged as having borderline significance (OR 0.4,
CI 0.1 to 1.1, p = 0.07). CONCLUSIONS: Vagal activation is more common in
women than in men during abrupt coronary occlusion and may have beneficial
antiarrhythmic effects, modifying the outcome of acute coronary events.
PMID: 9462571 [PubMed - indexed for MEDLINE]
13. Hully S, Grady D, Bush
T for the Heart and Estrogen/Progestin Replacement Study (HERS)
Research Group. Randomized trial of estrogen plus progestin
for secondary prevention of coronary heart disease in postmenopausal
women. J Am Med Assoc 1998; 280: 605–613.
14. Godsland IF, Wynn V, Crook D, Miller NE. Sex, plasma lipoproteins,
and atherosclerosis: prevailing assumptions and outstanding questions. Am Heart
J 1987; 114: 1467–1503.
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Role of ovarian hormones in the long-term
control of glucose homeostasis. Effects of insulin secretion.
Bailey CJ, Ahmed-Sorour H.
The role of ovarian hormones in the long-term control of B-cell function
of in the mouse has been examined. Ovariectomised adult female mice were
treated with daily subcutaneous replacement doses of oestradiol (5 microgram/kg),
progesterone (1 mg/kg), both hormones combined, or vehicle only for 15 weeks.
Ovariectomy caused a 40% increase in plasma glucose concentrations during
glucose tolerance tests, a 26% decrease in the plasma insulin response to
glucose (2 g/kg IP) and a 32% decrease in the plasma insulin response to
arginine (2 g/kg IP) compared with control mice. When islets from ovariectomised
mice were incubated for 30 minutes in media containing 28 mmol/l glucose
or 2.8 mmol/l glucose with 5 mmol/l arginine, insulin release was reduced
by 23% and 31% respectively. Total pancreatic and islet insulin content were
each decreased by 36%, and the number of B-cells was decreased by 39% in
the ovarietomised mice. These detrimental effects of ovariectomy were partially
or totally prevented by the oestradiol and progesterone treatments. The results
indicate that ovarian oestrogens and progestogens may play an important role
in the long-term maintenance of B-cell competence in the female mouse.
PMID: 7004967 [PubMed - indexed for MEDLINE]
16. Hale SL, Birnbaum Y, Kloner
RA. b-Estradiol, but not alpha-estradiol, reduced myocardial
necrosis in rabbits after ischemia and reperfusion. Am Heart
J 1996; 132: 258–262.
-
-
Myocardial protection of contractile
function after global ischemia by physiologic estrogen
replacement in the ovariectomized rat.
Kolodgie FD, Farb A, Litovsky SH, Narula J, Jeffers
LA, Lee SJ, Virmani R.
Department of Cardiovascular Pathology, Armed Forces Institute of Pathology,
Washington DC 20306-6000, USA.
The role of physiologic estrogen levels (pg) on post-ischemic myocardial
function was studied in the isolated working rat heart without (n=28, experiment
No. 1) or with (n=15, experiment No. 2) preconditioning. For experiment No.
1, female ovariectomized rats were treated with placebo (n=19) or 17beta-estradiol
(E2, n=9; chronic E2), and 14 days later hearts were removed and perfused
with modified Krebs-Henseleit buffer in vitro. In nine placebo-treated rats,
E2 was administered at 20 min prior to ischemia (acute E2). The hearts were
subjected to 15 min of global ischemia and 20 min of reflow. In experiment
No. 2, ovariectomized rats were treated with placebo (n=8) or 17beta-E2 (chronic
E2, n=7). In this experiment, hearts were first preconditioned and then subjected
to 20 min of sustained ischemia followed by 20 min of reflow. Global ischemia
was produced by clamping the aorta and restricting left atrial flow so that
coronary flow was reduced to zero; hemodynamics were continuously monitored
throughout the study. Aortic flow, coronary flow, cardiac output, and dP/dt
were assessed at baseline, at the end of the ischemic period, and during
reflow. The severity of ischemia was measured by post-ischemic release of
lactate, lactate dehydrogenase, and creatine kinase and was similar among
all groups in each study. In experiment No. 1, recovery of aortic flow, cardiac
output, and dP/dt following reperfusion, was significantly improved in rats
treated with chronic E2 (P<0.05); acute E2 had no significant benefit.
Post-ischemic recovery of coronary flow was not significantly affected. In
experiment No. 2, chronic E2 treatment also significantly improved post-ischemic
recovery of cardiac function in preconditioned hearts when compared with
controls (P<0. 05). In summary, E2 replacement in ovariectomized rats
improves contractile function following global ischemia and reflow; cardioprotection
by estrogen was observed over and above that conferred by ischemic preconditioning.
Since the cardioprotective effect of E2 was independent of a significant
improvement in coronary flow a direct effect of the hormone on the cardiac
myocytes is postulated. Copyright 1997 Academic Press Limited.
PMID: 9299364 [PubMed - indexed for MEDLINE]
18. Fraser H, Davidge ST, Clanachan AS. Enhancement of post-ischemic
myocardial function by chronic 17b-estradiol treatment: role of alterations
in glucose metabolism. J Mol Cell Cardiol 1999; 31: 1539–1549.
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Influence of age and menopause on serum
lipids and lipoproteins in healthy women.
Stevenson JC, Crook D, Godsland IF.
Wynn Institute for Metabolic Research, London UK.
Sex hormone deficiency is associated with increased coronary heart disease
(CHD) risk in women. We measured fasting serum lipids and lipoprotein concentrations
in a group of 542 healthy non-obese pre- and postmenopausal women (aged 18-70
years). Ageing was associated with increased concentrations of total cholesterol,
low density lipoprotein (LDL) cholesterol, high density lipoprotein subfraction
3 (HDL3) cholesterol and triglycerides, and decreased concentrations of high
density lipoprotein subfraction 2 (HDL2) cholesterol. Body mass index (BMI)
was related positively to concentrations of total and LDL cholesterol. Postmenopausal
women had significantly higher concentrations of total cholesterol (P < 0.001),
triglycerides (P < 0.005), LDL cholesterol (P < 0.001) and high density
lipoprotein subfraction 3 (HDL3) cholesterol (P < 0.001), whilst those
of HDL and HDL2 cholesterol were significantly lower (P < 0.001). These
differences were independent of age, BMI and other potential confounding
variables. We conclude that the menopause is associated with potentially
adverse changes in lipids and lipoproteins, independent of any effects of
ageing. These changes may in part explain the increased incidence of coronary
heart disease seen in postmenopausal women.
PMID: 8457253 [PubMed - indexed for MEDLINE
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Estrogen modulates responses of atherosclerotic
coronary arteries.
Williams JK, Adams MR, Klopfenstein HS.
Arteriosclerosis Research Center, Bowman Gray School of Medicine, Wake Forest
University, Winston-Salem, North Carolina 27103.
Although evidence indicates that estrogen replacement therapy reduces risk
of coronary heart disease, the mechanism remains unknown. Among the possibilities
are that estrogen replacement therapy may 1) inhibit growth of atherosclerotic
plaque and 2) decrease the prevalence of transient myocardial ischemia and
myocardial infarction by modulating vasomotion in atherosclerotic coronary
arteries. Using quantitative coronary angiography, we determined vasomotor
responses of atherosclerotic coronary arteries in ovariectomized cynomolgus
monkeys; six were given physiological estrogen "replacement" by
subcutaneous implants, and six were not. Intracoronary infusion of the endothelium-dependent
dilator acetylcholine (1 X 10(-6) M) caused paradoxical constriction of coronary
arteries (from 1.2 +/- 0.2 to 0.6 +/- 0.1 mm, p less than 0.05) in the estrogen-deficient
monkeys. However, acetylcholine tended to minimally dilate the left circumflex
coronary artery in estrogen-treated monkeys (from 1.2 +/- 0.2 to 1.5 +/-
0.2 mm, p greater than 0.2). Although estrogen replacement therapy reduced
plaque extent in coronary arteries, altered vasomotion was not related to
plaque extent. We conclude that estrogen modulates vasomotion of atherosclerotic
coronary arteries of monkeys and speculate that estrogen-modulated constrictor
responses of atherosclerotic coronary arteries may reduce the incidence of
coronary heart disease in postmenopausal women.
PMID: 2331772 [PubMed - indexed for MEDLINE
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Protection from myocardial reperfusion
injury by acute administration of 17 beta-estradiol.
Delyani JA, Murohara T, Nossuli TO, Lefer AM.
Department of Physiology, Jefferson Medical College, Thomas Jefferson University,
Philadelphia, PA 19107, USA.
Although several studies have demonstrated that chronic exposure to estrogen
appears to be cardioprotective, acute circulatory effects of estrogen are
largely unknown. Therefore, we studied the effects of acute administration
of 17 beta-estradiol in myocardial ischemia/reperfusion. Cats were subjected
to 90 min of left anterior descending coronary artery (LAD) occlusion and
270 min of reperfusion (MI/R). Either the estrogenic steroid, 17 beta-estradiol
or its non-estrogenic isomer, 17 alpha-estradiol was administered (i.v.)
30 min prior to reperfusion at 1 microgram/kg bolus followed by a constant
infusion lasting the remaining duration of the protocol at 1 microgram/kg/h.
Control cats were subjected to sham MI/R. Cats treated with 17 beta-estradiol
demonstrated a marked reduction in cardiac necrosis following MI/R compared
to cats receiving 17 alpha-estradiol or phosphate buffered saline (17 +/-
2% v 33 +/- 1% or 34 +/- 4% area of necrosis indexed to the area-at-risk,
P < 0.01). In addition, cats receiving 17 beta-estradiol exhibited reduced
myocardial PMN infiltration in necrotic tissue as compared to 17 alpha-estradiol
treated cats. Moreover, 17 beta-estradiol administration attenuated neutrophil
adherence to ex vivo coronary vascular endothelium compared to the two controls
(44 +/- 8 PMNs/mm2 v 79 +/- 7 PMNs/mm2 or 86 +/- 7 PMNs/mm2 P < 0.01).
These data indicate that 17 beta-estradiol protects against myocardial ischemia/reperfusion,
in part, by attenuating PMN infiltration and subsequent injury due to PMN
mediator release.
PMID: 8762038 [PubMed - indexed for MEDLINE.
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Both raloxifene and estrogen reduce
major cardiovascular risk factors in healthy postmenopausal
women: A 2-year, placebo-controlled study.
de Valk-de Roo GW, Stehouwer CD, Meijer P, Mijatovic
V, Kluft C, Kenemans P, Cohen F, Watts S, Netelenbos C.
Ageing Women Project: Department of Endocrinology, Research Institute for
Endocrinology, Reproduction, and Metabolism, University Hospital Vrije Universiteit,
Amsterdam, The Netherlands.
Currently raloxifene, a selective estrogen receptor modulator, is being investigated
as a potential alternative for postmenopausal hormone replacement to prevent
osteoporosis and cardiovascular disease. We compared the 2-year effects of
raloxifene on a wide range of cardiovascular risk factors with those of placebo
and conjugated equine estrogens (CEEs). Analyses were based on 56 hysterectomized
but otherwise healthy postmenopausal women aged 54. 8+/-3.5 (mean+/-SD) years
who entered this double-blind study and who were randomly assigned to raloxifene
hydrochloride 60 mg/d (n=15) or 150 mg/d (n=13), placebo (n=13), or CEEs
0.625 mg/d (n=15). At baseline and after 6, 12, and 24 months of treatment,
we assessed serum lipids, blood pressure, glucose metabolism, C-reactive
protein, and various hemostatic parameters. Compared with placebo, both raloxifene
and CEEs lowered the level of low density lipoprotein cholesterol by 0.53
to 0.79 mmol/L (all P<0.04) and lowered, at 24 months, the level of fibrinogen
by 0.71 to 0.86 g/L (all P<0.05). The effects of raloxifene and CEEs did
not differ significantly. In contrast to raloxifene, from 6 months on CEEs
increased high density lipoprotein cholesterol by 0.25 to 0.29 mmol/L and
reduced plasminogen activator inhibitor-1 antigen by 30.6 to 48.6 ng/mL (all
P<0.02 versus both placebo and raloxifene). CEEs transiently increased
C-reactive protein by 1.0 mg/L at 6 months (P<0.05 versus placebo) and
prothrombin-derived fragment F1+2 by 0. 79 nmol/L at 12 months (P<0.001
versus placebo). Finally, from 12 months on, CEEs increased triglycerides
by 0.33 to 0.56 mmol/L (all P<0.05 versus both placebo and raloxifene).
Our findings suggest that in healthy postmenopausal women, raloxifene and
estrogen monotherapy have similar beneficial effects on low density lipoprotein
cholesterol and fibrinogen levels. These treatments differ, however, in their
effects on high density lipoprotein cholesterol, triglycerides, and plasminogen
activator inhibitor-1 and possibly in their effects on prothrombin fragment
F1+2 and C-reactive protein.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 10591680 [PubMed - indexed for MEDLINE]
-
Multiple mechanisms are involved in
the acute vasodilatory effect of 17beta-estradiol in the
isolated perfused rat heart.
Hugel S, Neubauer S, Lie SZ, Ernst R, Horn M, Schmidt
HH, Allolio B, Reincke M.
Medizinische Universitatsklinik, Wurzburg, Germany.
The purpose of this study was to define the dose-dependent effects of 17beta-estradiol
on coronary flow and cardiac function in isolated rat hearts and to identify
the mechanisms involved in its vasodilator action. Hearts from female and
male Wistar rats were perfused at constant pressure (100 mm Hg). Stereoisomer
specificity and the mechanism of vasodilation by 17beta-estradiol were examined
in female rat hearts. Function was measured by a left ventricular (LV) balloon
and coronary flow (CF) with an ultrasonic flowmeter. 17Beta-estradiol at
10(-6), 5 x 10(-6), and 10(-5) M increased CF in female hearts by 5 +/- 2,
27 +/- 4 (p < 0.05 vs. baseline), and 40 +/- 4% (p < 0.05 vs. baseline),
respectively. The effect of 17beta-estradiol in hearts from male rats was
similar but less pronounced compared with females [deltaCF 8 +/- 3, 19 +/-
3 (p < 0.05 vs. baseline)] and 25 +/- 7% (p < 0.05 vs. baseline; p < 0.05
vs. female 17beta-estradiol). Maximum vasodilation by the stereoisomer 17alpha-estradiol
was significantly smaller [deltaCF 5 +/- 3, 4 +/- 3 (p < 0.05 vs. female
17beta-estradiol) and 14 +/- 1% (p < 0.05 vs. baseline; p < 0.05 vs.
female 17beta-estradiol)] for 10(-6), 5 x 10(-6), and 10(-5) M. Pretreatment
with the NO-synthesis inhibitor Nomega-methyl-L-arginine (10(-4) M) had no
effect on the maximal vasodilator response to 17beta-estradiol (10(-5) M)
[deltaCF 36 +/- 6% (p < 0.05 vs. baseline)]. When hearts were pretreated
with the prostaglandin-synthesis inhibitor diclofenac (10(-6) M), the maximal
vasodilator effect of 17beta-estradiol was partially attenuated [deltaCF
12 +/- 7% (p < 0.05 vs. female 17beta-estradiol)]. Similarly, pretreatment
with the K+ATP-blocker glibenclamide (10(-6) M) partially inhibited the maximal
vasodilator effect of 17beta-estradiol [deltaCF 22 +/- 6% (p < 0.05 vs.
baseline; p < 0.05 vs. female 17beta-estradiol)]. Pretreatment with the
Ca2+ channel antagonist nifedipine (7.2 x 10(-8) M) completely blocked the
vasodilator effect. In isolated perfused rat hearts, 17beta-estradiol induced
marked acute coronary vasodilation; this effect is in part gender specific,
and in female hearts, largely stereoisomer specific. The dilator effect is
mediated predominantly by calcium channel blockade, but prostaglandin release
and K+ATP channel activation also are involved. In the isolated perfused
rat heart, NO production does not contribute to the acute vasodilator effect
of 17beta-estradiol.
PMID: 10367587 [PubMed - indexed for MEDLINE.
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Acute effects of 17 beta-estradiol on
the coronary microcirculation: observations in sedated,
closed-chest domestic swine.
Berman M, Gewirtz H.
Department of Medicine, Rhode Island Hospital, Providence, USA.
OBJECTIVES: To test the hypotheses: that acute administration of 17 beta-estradiol
dilates normal coronary microvessels in vivo; that coronary microvascular
responses to acute estrogen stimulation exhibit sexual dimorphism; and that
nitric oxide has a role in mediating these effects. METHODS: Measurements
of hemodynamics, coronary flow velocity (Doppler), myocardial blood flow
(microspheres) and oxygen consumption were made in closed-chest swine: group
1 consisted of castrated juvenile males, groups 2 and 3 of estrogen pretreated,
castrated juvenile males, and group 4 of sexually mature females. 17 beta-Estradiol
(2, 20 or 200 ng/kg) was given by intracoronary injection and data obtained
20-30 min later; additional measurements were made 1 h after the 200 ng/kg
dose. The effect of L-NG-monomethylarginine (L-NMMA) on 17 beta-estradiol
responses was also tested. Tissue and blood concentrations of 17 beta-estradiol,
and concentrations of estrogen receptor in myocardium and coronary vessels
were obtained. RESULTS: In estrogen-naive castrated males, 17 beta-estradiol
had no effect on coronary flow velocity or myocardial blood flow, but 1 h
after the 200 ng/kg dose there was an increase in diastolic coronary resistance
compared with baseline (48 +/- 20 versus 41 +/- 17 mmHg/mkHz; P < 0.05).
Estrogen pretreated castrated males also showed no change in myocardial blood
flow after 17 beta-estradiol, but coronary flow velocity decreased (P < 0.05)
compared with baseline 1 h after the 200 ng/kg dose (from 1.69 +/- 0.61 to
1.41 +/- 0.42 kHz) and diastolic coronary resistance increased significantly
(P < 0.01) compared with control at this time (51 +/- 15 compared with
39 +/- 14 mmHg/mkHz). In sexually mature females, 17 beta-estradiol had no
effect on myocardial blood flow but did cause a significant (P < 0.05)
decrease in diastolic coronary vascular resistance compared with baseline
(51 +/- 9 mmHg/mkHz) at both the 20 ng/kg and the 200 ng/kg doses (both 43
+/- 11 mmHg/mkHz). Coronary flow velocity also increased (P < 0.06) compared
with baseline (1.34 +/- 0.26 mmHg/mkHz) after the 200 ng/kg dose (1.69 +/-
0.61 mmHg/mkHz). L-NMMA had no effect on flow responses to 17 beta-estradiol
in any group. Classical estrogen receptors were not present in myocardium
or coronary arteries from male or female swine. CONCLUSIONS: These results
demonstrate that 17 beta-estradiol exerts a mild constrictor effect on the
coronary microvessels of normal castrated, juvenile males whether estrogen-naive
or estrogen-pretreated. In contrast, sexually mature normal females exhibit
mild dilatation of the coronary microcirculation in response to acute estrogen
stimulation. Nitric oxide does not appear to have a role in mediating the
dilator response in females, and classical estrogen receptors are not involved.
A direct membrane effect of the hormone (perhaps via alteration in potassium
conductance) seems likely, and demonstrates sexual dimorphism.
PMID: 9347215 [PubMed - indexed for MEDLINE
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Induction of calcium-dependent nitric
oxide synthases by sex hormones.
Weiner CP, Lizasoain I, Baylis SA, Knowles RG, Charles
IG, Moncada S.
Wellcome Research Laboratories, Beckenham Kent, United Kingdom.
We have examined the effects of pregnancy and sex hormones on calcium-dependent
and calcium-independent nitric oxide synthases (NOSs) in the guinea pig.
Pregnancy (near term) caused a > 4-fold increase in the activity of calcium-dependent
NOS in the uterine artery and at least a doubling in the heart, kidney, skeletal
muscle, esophagus, and cerebellum. The increase in NOS activity in the cerebellum
during pregnancy was inhibited by the estrogen-receptor antagonist tamoxifen.
Treatment with estradiol (but not progesterone) also increased calcium-dependent
NOS activity in the tissues examined from both females and males. Testosterone
increased calcium-dependent NOS only in the cerebellum. No significant change
in calcium-independent NOS activity was observed either during pregnancy
or after the administration of any sex hormone. Both pregnancy and estradiol
treatment increased the amount of mRNAs for NOS isozymes eNOS and nNOS in
skeletal muscle, suggesting that the increases in NOS activity result from
enzyme induction. Thus both eNOS and nNOS are subject to regulation by estrogen,
an action that could explain some of the changes that occur during pregnancy
and some gender differences in physiology and pathophysiology.
PMID: 7515189 [PubMed - indexed for MEDLIN
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Estrogens increase transcription of
the human endothelial NO synthase gene: analysis of the
transcription factors involved.
Kleinert H, Wallerath T, Euchenhofer C, Ihrig-Biedert
I, Li H, Forstermann U.
Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany.
Estrogens have been found to reduce the incidence of cardiovascular disease
that has been ascribed in part to an increased expression and/or activity
of the vasoprotective endothelial NO synthase (NOS III). Some reports have
shown that the level of expression of this constitutive enzyme can be upregulated
by estrogens. The current study investigates the molecular mechanism of the
NOS III upregulation in human endothelial EA.hy 926 cells. Incubation of
EA.hy 926 cells with 17beta-estradiol or the more stable 17alpha-ethinyl
estradiol enhanced NOS III mRNA and protein expression up to 1.8-fold, without
changing the stability of the NOS III mRNA. There was no enhancement of NOS
III mRNA after incubation of EA.hy 926 cells with testosterone, progesterone,
or dihydrocortisol or when 17alpha-ethinyl estradiol was added together with
the estrogen antagonist RU58668, indicating a specific estrogenic response.
Nuclear run-on assays indicated that the increase in NOS III mRNA is the
result of an estrogen-induced enhancement of NOS III gene transcription.
In transient transfection experiments using a 1.6 kb human NOS III promoter
fragment (which contains no bona fide estrogen-responsive element, ERE),
basal promoter activity was enhanced 1.7-fold by 17alpha-ethinyl estradiol.
In electrophoretic mobility shift assays, nuclear extracts from estrogen-incubated
EA.hy 926 cells showed no enhanced binding activity either for the ERE-like
motif in the human NOS III promoter or for transcription factor GATA. However,
binding of transcription factor Sp1 (which is essential for the activity
of the human NOS III promoter) was significantly enhanced by estrogens. These
data suggest that the estrogen stimulation of the NOS III promoter could
be mediated in part by an increased activity of transcription factor Sp1.
PMID: 9461225 [PubMed - indexed for MEDLINE
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Gender difference in bioassayable endothelium-derived
nitric oxide from isolated rat aortae.
Kauser K, Rubanyi GM.
Cardiovascular Department, Berlex Biosciences, Richmond, California 94804.
Gender differences in the production/release of endothelium-derived nitric
oxide (EDNO) was assessed by determining the ability of intact endothelium
to suppress serotonin- (10(-7)-10(-5) M) and phenylephrine-induced (10(-9)-(10(-5)
M) contractions in thoracic aortae isolated from male and female Wistar rats
mounted in organ chambers for isometric tension recording or tested in bioassay
experiments. The endothelium suppressed these contractions significantly
more in aortae from female than from male rats. In the bioassay, the perfusate
from intact female thoracic aortic segments produced a significantly greater
relaxation of the detector rings than that from the aortae isolated from
male rats. Acetylcholine (10(-9)-10(-5) M), used to investigate agonist-induced
release of EDNO, evoked significantly greater endothelium-dependent relaxation
in aortae from female rats. The unstimulated release of 6-ketoprostaglandin
F1 alpha and thromboxane B2 from intact thoracic aortic rings from male and
female rats was not significantly different. There was no difference in smooth
muscle reactivity to sodium nitroprusside (10(-10)-10(-6) M) in rings without
endothelium. These results indicate that EDNO production/release is higher
in thoracic aortae isolated from female rats.
PMID: 7810731 [PubMed - indexed for MEDLINE
-
-
Serum vascular endothelial growth factor
concentrations in postmenopausal women: the effect of hormone
replacement therapy.
Agrawal R, Prelevic G, Conway GS, Payne NN, Ginsburg
J, Jacobs HS.
Department of Reproductive Endocrinology, The Middlesex Hospital and The
Royal Free Hospital, London, United Kingdom. ganapaty@dircon.co.uk
OBJECTIVE: To assess serum vascular endothelial growth factor (VEGF) concentrations
in healthy postmenopausal women in relation to hormone replacement therapy
(HRT) and the presence or absence of a uterus. DESIGN: Cross-sectional study.
SETTING: The Middlesex Hospital. PATIENT(S): A total of 199 postmenopausal
women were enrolled: 132 had uterus in situ and 67 had had hysterectomies.
Of the 67 women who had had hysterectomies, 6 received no HRT, 20 received
tibolone, 25 received transdermal E2, and 16 received conjugated equine estrogens.
Of the 132 women with uteri in situ, 34 received no HRT, 56 received tibolone,
24 received transdermal E2 with sequential norethisterone acetate, and 18
received conjugated equine estrogens with sequential levonorgestrel. INTERVENTION(S):
Serum VEGF level measurement. MAIN OUTCOME MEASURE(S): Serum VEGF concentrations.
RESULT(S): Women who received HRT had higher VEGF concentrations than those
not receiving HRT. Among women who received no HRT, those with uterus in
situ had higher VEGF levels than did those who had had hysterectomies. Among
women who had had hysterectomies, VEGF concentrations were higher in those
who received conjugated equine estrogens than in those who did not receive
HRT and those who received tibolone or transdermal E2. Among women with uterus
in situ, no difference was found between subgroups. CONCLUSION(S): Postmenopausal
women with uterus in situ and those who received HRT had higher VEGF concentrations
than did those who had had hysterectomies and who did not receive HRT. Among
women receiving HRT, those who received conjugated equine estrogens alone
had higher VEGF concentrations. This estrogen-mediated increase in serum
VEGF concentrations may be a mechanism by which HRT benefits the cardiovascular
system.
PMID: 10632412 [PubMed - indexed for MEDLI
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-
Atherosclerosis and the two faces of
endothelial nitric oxide synthase.
Wever RM, Luscher TF, Cosentino F, Rabelink TJ.
Department of Clinical Chemistry, University Hospital Utrecht, The Netherlands.
Publication Types:
PMID: 9443438 [PubMed - indexed for MEDLI
-
Induction and potential biological relevance
of a Ca(2+)-independent nitric oxide synthase in the myocardium.
Schulz R, Nava E, Moncada S.
Wellcome Research Laboratories, Langley Court, Beckenham, Kent.
1. We have investigated whether the myocardium and isolated cardiac myocytes
can express a Ca(2+)-independent NO synthase after treatment with endotoxin
or cytokines. Nitric oxide synthesis was measured in cytosols from the left
ventricular wall from rats treated with endotoxin, or from freshly isolated
myocytes from adult rats treated in vitro with cytokines. 2. Cytosols from
the ventricle of saline-treated control animals showed only Ca(2+)-dependent
NO synthesis. After treatment with endotoxin, the expression of an inducible,
Ca(2+)-independent NO synthase was observed. The activity of this enzyme
was maximal at 6 h and returned towards control levels by 18 h; no alterations
occurred in the Ca(2+)-dependent NO synthase activity. Parallel to this enzyme
induction there was an increase in myocardial guanosine 3':5'-cyclic monophosphate
(cyclic GMP) and plasma nitrite and nitrate (NOx-). All these changes were
prevented by pretreatment of the rats with dexamethasone. 3. Myocytes possessed
Ca(2+)-dependent NO synthase activity and expressed, after treatment with
tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta),
a Ca(2+)-independent NO synthase, the induction of which was prevented by
dexamethasone and cycloheximide. 4. Since increases in cyclic GMP levels
in the heart are associated with reduced myocardial contractility, it is
possible that the enhanced production of NO by a Ca(2+)-independent enzyme
accounts, at least in part, for the depression of myocardial contractility
seen in septic shock, cardiomyopathies, allograft rejection, burn trauma,
as well as during anti-tumour therapy with cytokines.
PMID: 1378338 [PubMed - indexed for MEDL
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Expression of oestrogen receptor alpha
and beta in rat heart: role of local oestrogen synthesis.
Grohe C, Kahlert S, Lobbert K, Vetter H.
Medizinische Universitats-Poliklinik, University of Bonn, Germany.
The role of cardiac oestrogen receptor expression and local oestrogen synthesis
in the pathogenesis of cardiovascular disease is poorly understood. Therefore
we studied the effects of the oestrogen precursors androstendione and testosterone
on the expression of cyp450 aromatase, oestrogen receptor alpha and beta,
and inducible NO synthase (iNOS) in neonatal rat cardiac myocytes. Here,
we show that cyp450 aromatase is expressed in cardiac myocytes and incubation
of cardiac myocytes with oestrogen precursors leads to sexual dimorphic transactivation
of an oestrogen-responsive reporter plasmid. Furthermore, incubation with
oestrogen precursors stimulated expression of oestrogen receptor alpha and
beta, and iNOS in a gender-specific fashion. These data suggest that local
oestrogen biosynthesis of the heart is effective to activate oestrogen receptor
alpha and beta, and downstream target genes in a gender-based fashion and
may therefore contribute to the beneficial effects of oestrogen in the pathogenesis
of cardiovascular disease.
PMID: 9518889 [PubMed - indexed for MEDLI
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Comment in:
Activation of Ca(2+)-independent nitric oxide synthase
by 17beta-estradiol in post-ischemic rat heart.
Fraser H, Davidge ST, Clanachan AS.
Department of Physiology, Faculty of Medicine and Dentistry, University of
Alberta, Edmonton, Canada.
BACKGROUND: Nitric oxide (NO) donors or facilitation of endogenous NO production
is cardioprotective. This study sought to determine whether enhanced myocardial
NO production might contribute to estrogen-induced cardioprotection. METHODS:
Ca(2+)-dependent and Ca(2+)-independent NOS activities (pmol min(-1) mg(-1)
protein), NOS protein expression (quantitative immunoblot), cGMP content
(pmol mg(-1) protein) and LV work (Joules) were measured in hearts isolated
from ovariectomized rats that were either untreated or treated chronically
with 17beta-estradiol (0.25 mg, 21 day release formulation). RESULTS: After
14 days, serum levels of 17beta-estradiol were 6+/-1 and 135+/-16 pg ml(-1)
in untreated and 17beta-estradiol-treated animals, respectively. After 60
min aerobic working mode perfusion, Ca(2+)-dependent NOS (untreated, 1.47+/-0.36;
17beta-estradiol 1.13+/-0.25) and Ca(2+)-independent NOS (untreated, 0.45+/-0.24;
17beta-estradiol, 0.41+/-0.21) activities, eNOS and iNOS proteins and cGMP
content (untreated, 0.64+/-0.08; 17beta-estradiol, 0.76+/-0.12) were not
different in the two groups. After 60 min low-flow (0.5 ml min(-1)) ischemia
and 30 min reperfusion, Ca(2+)-dependent NOS activities were again similar
(untreated, 1.25+/-0.23; 17beta-estradiol, 0.78+/-0.27). However, after reperfusion,
Ca(2+)-independent NOS activity (untreated, 0. 39+/-0.10; 17beta-estradiol,
1.36+/-0.36) was 3.5-fold higher (P=0. 008) and cGMP content (untreated,
0.30+/-0.03; 17beta-estradiol, 0. 49+/-0.07) was 1.6-fold higher (P=0.017)
in hearts from 17beta-estradiol-treated animals. Although pre-ischemic function
was similar, recovery of post-ischemic LV work was 2-fold greater (P=0.024)
in the 17beta-estradiol group. CONCLUSION: The ability of ischemia and reperfusion
in combination with chronic 17beta-estradiol to increase Ca(2+)-independent
NOS activity and cGMP content supports a role for enhanced myocardial NO
signaling in 17beta-estradiol-induced cardioprotection.
PMID: 10727659 [PubMed - indexed for MEDLI
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Cardiac efficiency is improved after
ischemia by altering both the source and fate of protons.
Liu B, Clanachan AS, Schulz R, Lopaschuk GD.
Department of Pediatrics, University of Alberta, Edmonton, Canada.
Cardiac efficiency is decreased in hearts after severe ischemia. We determined
whether reducing the production of H+ from glucose metabolism or inhibiting
the clearance of H+ via Na(+)-H+ exchange could increase cardiac efficiency
during reperfusion. This was achieved using dichloroacetate (DCA) to stimulate
glucose oxidation and 5-(N,N-dimethyl)-amiloride (DMA) to inhibit Na(+)-H+
exchange, respectively. Isolated working rat hearts were subjected to 30
minutes of global ischemia and 60 minutes of reperfusion. Glycolysis and
oxidation rates of glucose, lactate, and palmitate were measured. Recovery
of cardiac work, O2 consumption (MVO2), and rates of acetyl-coenzyme A and
ATP production during reperfusion were determined. After ischemia, cardiac
work recovered to 35 +/- 5% of preischemic values in control hearts (n =
23), although MVO2, tricarboxylic acid (TCA) cycle activity, and ATP production
from glycolysis and oxidative metabolism rapidly recovered to preischemic
levels. This decrease in cardiac efficiency was accompanied by a substantial
production of H+ from glucose metabolism DCA caused a 2.2-fold increase in
glucose oxidation, a 46 +/- 17% decrease in H+ production, a 1.6-fold increase
in cardiac efficiency, and a 2.0-fold increase in cardiac work during reperfusion
(n = 17). Inhibition of Na(+)-H+ exchange with DMA did not alter TCA cycle
activity and ATP production rates but did result in a 1.8-fold increase in
cardiac efficiency and a 1.7-fold increase in cardiac work (n = 12). These
data show that cardiac efficiency and the contractile function after ischemia
can be improved by either reducing the rate of H+ production from glucose
metabolism during reperfusion or inhibiting the clearance of H+ via Na(+)-H+
exchange. Our data suggest that an increased requirement for ATP to restore
ischemia-reperfusion-induced alterations in ion homeostasis contributes to
the decrease in cardiac efficiency and contractile function after ischemia.
PMID: 8888686 [PubMed - indexed for MED
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Overexpression of the cardiac Na+/Ca2+
exchanger increases susceptibility to ischemia/reperfusion
injury in male, but not female, transgenic mice.
Cross HR, Lu L, Steenbergen C, Philipson KD, Murphy
E.
National Institute of Environmental Health Sciences Research Triangle Park,
NC, USA. cross@niehs.nih.gov
Influx of Ca2+ into myocytes via Na+/Ca2+ exchange may be stimulated by the
high levels of intracellular Na+ and the changes in membrane potential known
to occur during ischemia/reperfusion. This increased influx could, in turn,
lead to Ca2+ overload and injury. Overexpression of the cardiac Na+/Ca2+
exchanger therefore may increase susceptibility to ischemia/reperfusion injury.
To test this hypothesis, the hearts of male and female transgenic mice, overexpressing
the Na+/Ca2+ exchange protein, and hearts of their wild-type littermates,
were perfused with Krebs-Henseleit buffer and subjected to 20 minutes of
ischemia and 40 minutes of reperfusion. Preischemic left ventricular developed
pressures and +dP/dtmax, as well as -dP/dtmin, were higher in the male transgenic
hearts compared with wild-type, implying a role for Na+/Ca2+ exchange in
the contraction, as well as the relaxation, phases of the cardiac beat. Postischemic
function was lower in male transgenic than in male wild-type hearts (7+/-2%
versus 32+/-6% of preischemic function), but there was no difference between
female transgenic and female wild-type hearts, both at approximately 30%
of preischemic function. To assess whether this male/female difference was
due to female-specific hormones such as estrogen, the hearts of bilaterally
ovariectomized and sham-operated transgenic females were subjected to the
same protocol. The functional recoveries of ovariectomized female transgenic
hearts were lower (17+/-3% of preischemic function) than those of wild-type
and sham-operated transgenic females. The lower postischemic functional recovery
in the male transgenic and female ovariectomized transgenic hearts correlated
with lower recoveries of the energy metabolites, ATP and phosphocreatine,
as measured by 31P nuclear magnetic resonance spectroscopy. Alternans were
observed during reperfusion in male transgenic and female ovariectomized
transgenic hearts only, consistent with intracellular Ca2+ overload. Western
analyses showed that alterations in the expression of the Na+/Ca2+ exchange
or L-type Ca2+ channel proteins were not responsible for the protection observed
in the female transgenic hearts. In conclusion, in males, overexpression
of the Na+/Ca2+ exchanger reduced postischemic recovery of both contractile
function and energy metabolites, indicating that the Na+/Ca2+ exchanger may
play a role in ischemia/reperfusion injury. From the studies of females,
however, it appears that this exacerbation of ischemia/reperfusion injury
by overexpression of the Na+/Ca2+ exchanger can be overcome partially by
female-specific hormones such as estrogen.
PMID: 9851938 [PubMed - indexed for MEDL
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Effects of natural and synthetic estrogens
and progestins on glycogen deposition in female mice.
Carrington LJ, Bailey CJ.
Glycogen deposition and glucose tolerance were examined in female mice after
24 days of oral treatment with natural (17 beta-estradiol and progesterone)
and synthetic (ethinyl estradiol and norethisterone acetate) sex steroids,
administered individually and in estrogen-progestin combination. Doses were
5 micrograms/kg/day for estrogens and 1 mg/kg/day for progestins. Compared
with diestrus control mice, each treatment increased glycogen deposition
in liver, uterus, heart and biceps femoris muscle. 17 beta-Estradiol produced
the greatest increments. Progesterone produced considerably smaller increments
and antagonized the glycogenic effects of 17 beta-estradiol. Ethinyl estradiol
and norethisterone acetate generally induced similar changes in glycogen
deposition. Treatments containing 17 beta-estradiol improved glucose tolerance.
Although glucose tolerance was not significantly altered by the other sex
steroid treatments, the changes in glycogen deposition indicate important
effects on tissue carbohydrate metabolism.
PMID: 3997066 [PubMed - indexed for ME
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Effect of estradiol on tissue glycogen
metabolism in exercised oophorectomized rats.
Kendrick ZV, Steffen CA, Rumsey WL, Goldberg DI.
Biokinetics Research Laboratory, College of Health, Physical Education, Recreation,
and Dance, Temple University, Philadelphia, Pennsylvania 19122.
The effect of both physiological and pharmacological doses of estradiol on
exercise performance and tissue glycogen utilization was determined in oophorectomized
estradiol-replaced (ER) rats. Doses of beta-estradiol 3-benzoate (0.02, 0.04,
0.1, 0.2, 1, 2, 4, or 10 micrograms.0.1 ml of sunflower oil-1.100 g body
wt-1) were injected 5 days/wk for 4 wk. Controls were sham injected (SI).
After treatment, the animals were run to exhaustion on a motorized treadmill.
ER animals receiving the 0.02-microgram dose ran significantly longer and
completed more total work than the SI group. ER animals receiving doses of
greater than or equal to 0.04 microgram ran longer and performed more work
than the 0.02-microgram group. At exhaustion, myocardial glycogen content
was significantly decreased in animals that were ER with less than or equal
to 0.1 microgram, whereas those replaced with doses greater than 0.1 microgram
utilized significantly less glycogen. With the 10-micrograms dose no significant
decrease in heart glycogen content was observed at exhaustion. A submaximal
2-h run significantly reduced glycogen content in heart, red and white portions
of the vastus lateralis, and the livers of SI animals. The latter effect
was attenuated in skeletal muscle and liver, and there was no effect in the
hearts of the ER animals receiving 2 micrograms. These data indicate that
estradiol replacement in oophorectomized rats influenced myocardial glycogen
utilization during exhaustive exercise and spared tissue glycogen during
submaximal exercise. These glycogen sparing effects may have contributed
to the significant improvements in exercise performance observed in this
study.
PMID: 3654408 [PubMed - indexed for ME
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A gender-related defect in lipid metabolism
and glucose homeostasis in peroxisome proliferator- activated
receptor alpha- deficient mice.
Djouadi F, Weinheimer CJ, Saffitz JE, Pitchford C, Bastin
J, Gonzalez FJ, Kelly DP.
INSERM U319, Universite Paris 7, Paris, France.
The peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear
receptor implicated in the control of cellular lipid utilization. To test
the hypothesis that PPARalpha is activated as a component of the cellular
lipid homeostatic response, the expression of PPARalpha target genes was
characterized in response to a perturbation in cellular lipid oxidative flux
caused by pharmacologic inhibition of mitochondrial fatty acid import. Inhibition
of fatty acid oxidative flux caused a feedback induction of PPARalpha target
genes encoding fatty acid oxidation enzymes in liver and heart. In mice lacking
PPARalpha (PPARalpha-/-), inhibition of cellular fatty acid flux caused massive
hepatic and cardiac lipid accumulation, hypoglycemia, and death in 100% of
male, but only 25% of female PPARalpha-/- mice. The metabolic phenotype of
male PPARalpha-/- mice was rescued by a 2-wk pretreatment with beta-estradiol.
These results demonstrate a pivotal role for PPARalpha in lipid and glucose
homeostasis in vivo and implicate estrogen signaling pathways in the regulation
of cardiac and hepatic lipid metabolism.
PMID: 9739042 [PubMed - indexed for ME
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Ranolazine stimulates glucose oxidation
in normoxic, ischemic, and reperfused ischemic rat hearts.
McCormack JG, Barr RL, Wolff AA, Lopaschuk GD.
Department of Pediatrics, University of Alberta, Edmonton, Canada.
BACKGROUND: Ranolazine is a novel antianginal agent that may reduce symptoms
without affecting hemodynamics and has shown cardiac antiischemic effects
in in vivo and in vitro models. In one study it increased active pyruvate
dehydrogenase (PDHa). Other agents that increase PDHa and so increase glucose
and decrease fatty acid (FA) oxidation are beneficial in ischemic-reperfused
hearts. Effects of ranolazine on glucose and palmitate oxidation and glycolysis
were assessed in isolated rat hearts. METHODS AND RESULTS: Working hearts
were perfused with Krebs-Henseleit buffer plus 3% albumin under normoxic
conditions and on reperfusion after 30-minute no-flow ischemia and under
conditions designed to give either low [low (Ca) (1.25 mmol/L), high [FA]
(1.2 mmol/L palmitate; with/without insulin] or high (2.5 mmol/L Ca, 0.4
mmol/L palmitate; with/without pacing) glucose oxidation rates; Langendorff-perfused
hearts (high Ca, low FA) were subjected to varying degrees of low-flow ischemia.
Glycolysis and glucose oxidation were measured with the use of [5-3H/U-14C]-glucose
and FA oxidation with the use of [1-14C]- or [9,10-3H]-palmitate. In working
hearts, 10 micromol/L ranolazine significantly increased glucose oxidation
1.5-fold to 3-fold under conditions in which the contribution of glucose
to overall ATP production was low (low Ca, high FA, with insulin), high (high
Ca, low Fa, with pacing), or intermediate. In some cases, reductions in FA
oxidation were seen. No substantial changes in glycolysis were noted with/without
ranolazine; rates were approximately 10-fold glucose oxidation rates, suggesting
that pyruvate supply was not limiting. Insulin increased basal glucose oxidation
and glycolysis but did not alter ranolazine responses. In normoxic Langendorff
hearts (high Ca, low FA; 15 mL/min), all basal rates were lower compared
with working hearts, but 10 micromol/L ranolazine similarly increased glucose
oxidation; ranolazine also significantly increased it during flow reduction
to 7, 3, and 0.5 mL/min. Ranolazine did not affect baseline contractile or
hemodynamic parameters or O2 use. In reperfused ischemic working hearts,
ranolazine significantly improved functional outcome, which was associated
with significant increases in glucose oxidation, a reversal of the increased
FA oxidation seen in control reperfusions (versus preischemic), and a smaller
but significant increase in glycolysis. CONCLUSIONS: Beneficial effects of
ranolazine in cardiac ischemia/reperfusion may be due, at least in part,
to a stimulation of glucose oxidation and a reduction in FA oxidation, allowing
improved ATP/O2 and reduction in the buildup of H+, lactate, and harmful
fatty acyl intermediates.
PMID: 8616920 [PubMed - indexed for ME
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Comment on:
Glucose metabolism in the ischemic heart.
Lopaschuk GD, Stanley WC.
Publication Types:
- Comment
- Editorial
- Review
- Review, Tutorial
PMID: 9008441 [PubMed - indexed for MEDLINE]
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