Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Susceptibility to drug-induced coronary vasospasm in rhesus monkeys increases after removal of the ovaries and can be normalized by adding back physiological levels of estradiol-17ss (E2) and/or natural progesterone (P) in vivo as reported recently by our group. Furthermore, the reactivity status (Ca2+ and protein kinase C responses) of freshly isolated and primary culture coronary artery vascular muscle cells (VMC) mimic the intact coronary artery responses to 5-HT + U46619. Since coronary reactivity is maintained in the isolated VMC, we hypothesized that the reactivity state inherent in the VMC was modulated directly by ovarian steroids in vitro as in the whole animal. To test this hypothesis, we treated hyperreactive VMC from ovariectomized (ovx) monkeys in vitro with E2 or P and measured VMC reactivity to combined stimulation with 5-HT and U46619, as determined by the amplitude and especially the duration of intracellular Ca2+ signals, as well as protein kinase C (PKC) activation/translocation. VMC were treated for 12 96 h with 3 100 pg/ml E2 (10 365 pM) and/or 0.3 3 ng/ml P (0.95 9.5 nM). Hyperreactive responses to the combination of 5-HT and U46619 in untreated VMC were significantly and dose-dependently reduced by treatment in vitro with physiological levels of either E2 or P for at least 24 h. Both the early transient and late sustained increases in intracellular Ca2+ and PKC translocation were blunted, and the effects of 0.2 nM E2 and 3.2 nM P were specifically antagonized by the receptor blockers ICI 182,780 (200 nM) and RU486 (15 nM), respectively. Antibodies to the estrogen receptor and progesterone receptor labeled nuclei in VMC, which were also positively labeled by a smooth muscle myosin heavy chain monoclonal antibody. These data indicate that natural ovarian steroids directly reduce hyperreactive 5-HT and thromboxane A2-stimulated Ca2+ and PKC responses of coronary artery VMC from surgically menopausal rhesus macaques. We hypothesize that vascular hyperreactivity, which may be a critical factor involved in the increased incidence of coronary artery vasospasm and ischemic heart disease in postmenopausal women, can be normalized by E2 and/or P through direct actions on coronary artery vascular muscle cells.
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PMID:In vitro modulation of primate coronary vascular muscle cell reactivity by ovarian steroid hormones. 976 86

We investigated the function of estrogen receptor-alpha in global myocardial ischemia and reperfusion injury in male estrogen receptor-alpha knockout (ERKO) and wild-type mice. Mouse hearts were subjected to 45 min of global ischemia followed by 180 min of reperfusion. The hearts were excised, cannulated, and maintained in a chilled (4 degrees C) cardioplegia solution until warm (37 degrees C) oxygenated Krebs-Henseleit bicarbonate buffer was perfused through the coronary arteries. ERKO hearts started beating later and had a higher incidence of ventricular fibrillation and/or tachycardia than control hearts. Coronary flow rate was significantly lower in ERKO hearts during the 90- and 120-min periods of reperfusion. Ca(2+) accumulation was significantly greater following 30, 90, 120, 150, and 180 min of reperfusion in ERKO hearts. Nitrite production was significantly less in ERKO hearts following 90, 120, and 150 min of reperfusion. Myocardial reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was significantly lower in experimental ERKO hearts. Marked interstitial edema and contraction bands were seen in hematoxylin-eosin-stained sections of ischemia-reperfused ERKO hearts but not in control tissues. Hematoxylin-basic fuchsin-picric acid-stained sections from experimental ERKO hearts had fewer viable myocytes compared with controls. Transmission electron microscopy revealed swollen and fragmented mitochondria with amorphous and granular bodies, loss of matrix, and rupture of cristae in experimental ERKO hearts. This is the first demonstration that estrogen receptor-alpha plays a cardioprotective role in ischemia-reperfusion injury in males.
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PMID:Myocardial ischemia-reperfusion injury in estrogen receptor-alpha knockout and wild-type mice. 1077 44

In every year since 1984, cardiovascular disease has claimed the lives of more females than males. More than 450,000 women succumb to heart disease annually, and 250,000 die of coronary artery disease. Despite the proportions, most women believe they will die of breast cancer. The perception that heart disease is a man's disease and that women are more likely to die of breast cancer is alarming. Although women develop heart disease about 10 years later than men, they are likely to fare worse after a heart attack. The poorer outcomes are due, in part, to the failure to identify heart attack symptoms. Approximately 35% of heart attacks in women are believed to go unnoticed or unreported. However, because of increased age, women are more likely to have co-morbid diseases such as diabetes and hypertension. In women, not only is "tightness" or discomfort in the chest a warning sign, but in addition, nausea and dizziness are common indicators of myocardial ischemia. Other symptoms include breathlessness, perspiration, a sensation of fluttering in the heart, and fullness in the chest. In comparison to men, women are less likely to undergo tertiary care interventions such as cardiac catheterization, angioplasty, thrombolytic therapy, and bypass surgery; to participate in cardiac rehabilitation; and to return to work full-time after myocardial infarction. In the past, most research about treatments for heart disease focused on men, and gender differences have been ignored. Recent studies are enrolling enough women to test if there are differences between men and women in outcomes. One of the major areas of research relates to estrogen and hormonal replacement therapy to reduce the relative risk of heart attack and stroke. The Women's Health Initiative is a major NIH-sponsored trial that addresses the issue of primary prevention of cardiac disease by hormonal replacement therapy. The results will be available in 2004. The Heart Estrogen/Progestin Replacement Study (HERS), disappointingly, did not show a significant reduction of coronary events in women taking hormonal replacement therapy, nor did the Estrogen Replacement and Atherosclerosis (ERA) trial of 309 postmenopausal women who underwent coronary angiography. New insight into the role of vitamins, phytoestrogens and other natural sources, and selective estrogen receptor modulators may provide other options for management. Until then, modification of risk factors and healthy life style choices are recommended for reducing the risk of cardiac disease. In fact, the key to a healthy heart in the year 2000 appears closely tied to life style choices. Prevention of disease is the key, and current recommendations are simply to stop smoking, or do not start; treat and control blood pressure >140/90 mm Hg; manage elevated lipids by diet, exercise, and cholesterol-lowering medications (if necessary); treat diabetes; lose weight so that BMI is <25; walk for 20-30 minutes at least three times a week; and take an aspirin tablet daily.
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PMID:Heart disease in women. 1114 May 44

Platelets play an important role in the coronary thrombus formation that leads to myocardial ischemia and infarction. Gender differences in the development of coronary heart disease and its outcomes are partly regulated by estrogen and its receptors, but the roles of the latter in thrombogenicity are less well-defined. We previously demonstrated the presence of estrogen receptor (ER) beta in cells of the megakaryocytic lineage. In this study, we characterize human platelet ERbeta and its expression using biochemical and molecular biological techniques. Western immunoblotting showed that platelet ERbeta migrated with an apparent molecular mass approximately 3.7 kDa larger than ERbeta in a variety of cell lines (including those of prostate and breast origin). A rigorous investigation of platelet ERbeta mRNA by reverse transcriptase-polymerase chain reaction revealed normal transcripts and a single alternately spliced mRNA. However, this variant form was smaller, lacking exon 2, and could not account for the larger protein size seen in platelets. Treatment of ERbeta with N-glycosidase F, which removes core carbohydrate residues, caused a more rapid migration through polyacrylamide gels but had no effect on ERbeta from human cell lines. We conclude that the larger form of ERbeta in human platelets is not attributable to alternate mRNA splicing but primarily to tissue-specific glycosylation.
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PMID:Human platelets contain a glycosylated estrogen receptor beta. 1123 Jan 12

The continued widespread prevalence of breast cancer supports placing a high priority on research aimed at its primary prevention, particularly among women who are at increased risk for developing this disease. The suggestion of potential agents for the primary chemoprevention of breast cancer evolved out of the treatment setting. Extensive experience with tamoxifen, a first-generation selective estrogen receptor modulator (SERM) showing efficacy, first, in the treatment of advanced breast cancer and, subsequently, as adjuvant therapy for early stage disease established the safety of this agent. Cumulative data from multiple adjuvant studies documented the efficacy of tamoxifen in reducing second primary breast cancers in the contralateral breast, supporting its potential as a chemopreventive agent for breast cancer. The safety and second primary data on tamoxifen, together with extensive information on its pharmacokinetics, metabolism, and antitumor effects, as well as its potentially beneficial effects on lipid metabolism and osteoporosis, led the National Surgical Adjuvant Breast and Bowel Project (NSABP) to select tamoxifen for testing in the first prospective randomized phase III trial of the efficacy of a chemopreventive agent for preventing breast cancer in women at increased risk of the disease. Accordingly, in 1992 the NSABP started the Breast Cancer Prevention Trial (P-1) in which 13,388 women > or = 35 years of age who were at increased risk of breast cancer according to Gail model risk factors [family history, age, and personal history (i.e., age at first birth, age at menarche, previous breast biopsies)] were randomized to tamoxifen 20 mg/day or placebo for 5 years. Through 69 months of follow-up tamoxifen reduced the risk of invasive breast cancer, primarily estrogen receptor-positive tumors, by 49% (two-sided p < 0.00001). Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided p < 0.002). In addition, tamoxifen reduced fractures of the hip, radius, and spine, but it had no effect on the rate of ischemic heart disease. As previously shown, the rates of endometrial cancer and vascular events increased with tamoxifen. With the P-1 results establishing tamoxifen as the standard of care for the primary chemoprevention of breast cancer in high-risk women, concern over the side effects of tamoxifen has prompted a continuing search for an agent that displays a more desirable efficacy/toxicity profile. Raloxifene, a second-generation SERM approved for the prevention of osteoporosis in postmenopausal women, displays antiestrogenic properties in the breast and possibly the endometrium, and estrogenic effects in the bone and on the lipid profile, suggesting it as a candidate for comparison with the chemopreventive standard, tamoxifen. Raloxifene will be compared to tamoxifen in an equivalency trial, the Study of Tamoxifen and Raloxifene (STAR) NSABP P-2, which began in July 1999 at almost 500 centers in North America. The plan is to randomize 22,000 postmenopausal women > or = 35 years of age at increased risk of breast cancer by Gail criteria to tamoxifen 20 mg/day or raloxifene 60 mg/day for 5 years. Study endpoints include invasive and noninvasive breast cancer, cardiovascular disease, endometrial cancer, bone fractures, and vascular events.
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PMID:From adjuvant therapy to breast cancer prevention: BCPT and STAR. 1146 26

We investigated the effects of phytoestrogen on global myocardial ischemia-reperfusion injury in five groups of female rats. A high-phytoestrogen group (HPE) was ovariectomized (Ovx) and fed a diet containing soybean protein and a high-isoflavone soy extract. Another Ovx group of rats was fed the same diet as the HPE group but treated with the estrogen receptor blocker ICI-182,780 (HPE + ICI). A third group of Ovx rats was fed a diet containing soybean protein alone (low-phytoestrogen content; LPE). A fourth Ovx group was fed a diet free of phytoestrogen (Ovx). The fifth group of rats was sham ovariectomized (sham). Hearts from all rats were subjected to 30 min of global, hypothermic (4 degrees C), cardioplegic ischemia and 120 min of normothermic (37 degrees C) reperfusion with oxygenated Krebs-Henseleit buffer. Compared with either the sham or the HPE group, the Ovx and HPE + ICI groups had significantly decreased first derivative of left ventricular pressure (dP/dt), coronary flow rate (CFR), nitrite production and mitochondrial respiratory function and significantly increased Ca2+ accumulation and myocardial histological and ultrastructural injury. The CFR of the LPE group was significantly different from that of either Ovx or HPE + ICI group but the dP/dt, nitrite production, Ca2+ accumulation, and mitochondrial function were not. Our results indicate that diets containing phytoestrogen extract play a cardioprotective role in global myocardial ischemia-reperfusion in female rats.
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PMID:Effects of dietary phytoestrogen on global myocardial ischemia-reperfusion injury in isolated female rat hearts. 1151 91

The role of estrogen in altering cardiovascular disease risk in women is contentious. Menopause is associated with increased risk for ischemic heart disease and cerebrovascular disease, which collectively are the main causes of morbidity and mortality in women of developed nations. Observational studies suggest a protective role of estrogen, whereas recent randomized controlled trials report a negative role for oral estrogen in primary and secondary prevention of cardiovascular events. Inflammatory mechanisms underlie the process of arterial thrombus formation following atheromatous plaque rupture, and as such modulation of the inflammatory process may be a potential means of reducing cardiovascular risk. Sex steroids may influence inflammatory processes and hence modify cardiovascular risk. The objective of the study was to review the current understanding of the relationships between C-reactive protein (CRP), homocysteine, IL-6, and lipoprotein (a) [Lp(a)] and endogenous estrogen status, exogenous estrogen treatment, and cardiovascular disease risk. The design was a review of all relevant published, peer- reviewed studies. Raised levels of CRP, homocysteine, Lp(a), IL-6, and CRP are each independently associated with increased risk for cardiovascular events in women. Changes in these parameters across the menopausal transition cannot clearly be attributed to hormonal changes. With respect to the effects of exogenous postmenopausal therapy, oral estrogen use is consistently associated with elevations in CRP, no change or a reduction in homocysteine, varied effects on IL-6, and a consistent reduction in Lp(a). Transdermal estradiol overall has no significant effect on any of these parameters. Progestin use appears to attenuate the effect of oral estrogen on CRP and is associated with a reduction in Lp(a). Like oral estrogen, tibolone use is associated with a rise in CRP, with no change in homocysteine and consistent lowering of Lp(a). Selective estrogen receptor modulators modestly lower homocysteine and Lp(a), have varied effects on CRP, and have no reported effects on IL-6. Despite these varied effects of postmenopausal hormone treatment on inflammatory markers, homocysteine, and Lp(a), there is no evidence that change in these markers results in modification of cardiovascular risk. Further studies are required to specifically investigate whether treatments that increase or decrease these markers in fact modulate the risk of cardiovascular events in women.
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PMID:New markers for cardiovascular disease risk in women: impact of endogenous estrogen status and exogenous postmenopausal hormone therapy. 1278 42

The purpose of this study is to examine whether raloxifene, one of the selective estrogen receptor modulators, could improve myocardial ischemia and to assess the mechanisms involved. In open-chest beagle dogs anesthetized by intravenous infusion of sodium pentobarbital, the left anterior descending coronary artery (LAD) was perfused from the left carotid artery through an extracorporeal bypass tube. Raloxifene was infused into the LAD through the bypass tube under either ischemic or non-ischemic conditions. In the non-ischemic heart, raloxifene had no effect on coronary blood flow, fractional shortening, and myocardial metabolism. However, raloxifene caused an acute increase in both coronary blood flow and fractional shortening, and also improved myocardial anaerobic metabolism in the ischemic heart. These effects were partially attenuated by pretreatment with either L-NAME or wortmannin and were completely abolished by ICI182780 (an estrogen receptor antagonist) or L-NAME plus charybdotoxin (a blocker of Ca-activated K channels). Raloxifene also increased both Akt activity and the NO level, with these changes being completely abrogated by pretreatment with wortmannin. These results demonstrated that raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism by release of NO and opening of Ca-activated K channels in the ischemic heart, and that NO production is mediated by the phosphatidylinositol 3-kinase/Akt pathway.
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PMID:Raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism in the ischemic heart: role of phosphatidylinositol 3-kinase/Akt pathway. 1516 76

Cyclovirobuxine D is an active compound extracted from Buxus microphylla, which has been used for treating acute myocardial ischemia in China. The present study was to investigate its mechanism on myocardial ischemia. Cyclovirobuxine D significantly increased cardiomyocytes viability injured by oxidation or hypoxia. It significantly reduced the infarct size induced by ligating the coronary artery in rats, and the effect was almost abolished by glibenclamide, a blocker of ATP sensitive potassium channel, but it was not influenced by cyclooxygenase-2 inhibitor celecoxib or estrogen receptor antagonist tamoxifen. In addition, cyclovirobuxine D significantly protected rat aorta endothelial cells against hypoxia and enhanced nitric oxide (NO) release from endothelial cells, which was inhibited by nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME). Furthermore, cyclovirobuxine D significantly decreased the weight of venous thrombus in rats. In conclusion, the action mechanism of cyclovirobuxine D on myocardial ischemia may be related with its cytoprotection, K(ATP) channel opening, NO generation stimulating and venous thrombosis inhibiting.
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PMID:Cyclovirobuxine D ameliorates acute myocardial ischemia by K(ATP) channel opening, nitric oxide release and anti-thrombosis. 1755 43

Estrogens are known to contribute to endothelial function and sympathetic activity, both of which are strongly associated with the pathogenesis of ischemic heart disease. In addition, estrogens improve impaired lipid profile, a risk factor of endothelial dysfunction. In this study, we investigated the effects of OS-0544, a structurally new selective estrogen receptor modulator (SERM), on endothelial function, sympathetic activity, and plasma cholesterol level in ovariectomized (OVX) rats. Female Sprague-Dawley rats were ovariectomized and orally treated with OS-0544 (or OS-0689, the (R)-enantiomer of OS-0544), or 17beta-estradiol (E2) for 4 weeks, starting the next days after ovariectomy or for 1 week, starting 6 weeks after ovariectomy. Ovariectomy significantly increased vasopressin-induced mean blood pressure (AVP-MBP) (57+/-3.3 mm Hg vs. 46+/-3.5 mm Hg, P<0.05) and decreased acetylcholine (Ach)-induced maximum vasorelaxation response (69+/-5.6% vs. 81+/-4.0%, P<0.05). OS-0544 significantly inhibited AVP-MBP elevation (46+/-3.5 mm Hg vs. 57+/-3.3 mm Hg, P<0.05) and decreased Ach-induced maximum vasorelaxation response (90+/-3.3% vs. 69+/-5.6%, P<0.05) in OVX rats. In addition, OS-0689 as well as E2 significantly reduced (up to 67%) the increase in sympathetic activity in OVX rats. Moreover, like E2, OS-0544 significantly decreased plasma cholesterol level in OVX rats. These results demonstrate that OS-0544 has vascular protective effect on vascular function after ovariectomy. It is therefore believed that OS-0544 has vascular protective effect in postmenopausal woman.
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PMID:Effect of OS-0544, a selective estrogen receptor modulator, on endothelial function and increased sympathetic activity in ovariectomized rats. 1885 27


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