Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The JCR:LA-cp rat is obese and insulin resistant and develops a major vasculopathy, with associated ischemic damage to the heart. Male rats were treated with 17alpha-ethinylestradiol (EE), LY117018, and/or the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). LY117018 decreased plasma cholesterol esters, with a 40% reduction in total cholesterol. EE increased triglyceride levels and modestly decreased cholesterol esters. L-NAME increased blood pressure and aortic contractile sensitivity to phenylephrine and inhibited acetylcholine-induced relaxation. LY117018 decreased the force of contraction. The L-NAME-mediated increase in force of contraction and decrease in response to acetylcholine was inhibited by LY117018. L-NAME-induced hypertension was prevented by LY117018. Platelet aggregation was not different between obese and lean rats and was unaffected by L-NAME. LY117018, both in the absence and presence of L-NAME, inhibited platelet aggregation. The effects of LY117018 are apparently mediated through both NO-dependent and -independent mechanisms. The changes induced by EE and LY117018 may reflect the activation of multiple mechanisms, both estrogen receptor-dependent and -independent. The changes induced by LY117018 are significant and may prove to be cardioprotective in the presence of the insulin resistance syndrome.
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PMID:Effects of LY117018 and the estrogen analogue, 17alpha-ethinylestradiol, on vascular reactivity, platelet aggregation, and lipid metabolism in the insulin-resistant JCR:LA-cp male rat: role of nitric oxide. 1115 69

Estradiol inhibits endothelin-1 synthesis, an effect that may contribute to the cardiovascular protective effects of estradiol. Recent findings that estradiol inhibits neointima formation in mice lacking estrogen receptors suggests that the cardiovascular protective effects of estradiol may be mediated by means of an estrogen receptor-independent mechanism. Because 2-hydroxyestradiol and 2-methoxyestradiol, metabolites of estradiol with little/no affinity for estrogen receptors, are more potent than estradiol in inhibiting vascular smooth muscle cell growth, we investigated whether these metabolites also inhibit endothelin-1 synthesis by means of an receptor-independent mechanism. Treatment of porcine coronary artery endothelial cells for 4 to 24 hours with 0.001 to 1 micromol/L of estradiol, 2-hydroxyestradiol, or 2-methoxyestradiol concentration-dependently inhibited basal as well as serum-induced (2.5%), TNFalpha-induced (10 ng/mL), angiotensin II-induced (100 nmol/L), and thrombin-induced (4 U/mL) endothelin-1 synthesis. Estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol also inhibited serum-induced mitogen-activated protein kinase activity. As compared with estradiol, its metabolites were more potent in inhibiting endothelin-1 secretion and mitogen activated protein kinase activity. The inhibitory effects of 2-hydroxyestradiol and 2-methoxyestradiol on endothelin-1 release and mitogen-activated protein kinase activity were not blocked by ICI182780 (50 micromol/L), an estrogen receptor antagonist. Our findings indicate that the estradiol metabolites 2-hydroxyestradiol and 2-methoxyestradiol potently inhibit endothelin-1 synthesis by means of an estrogen receptor-independent mechanism. This effect of estradiol metabolites may be mediated by inhibition of mitogen activated protein kinase activity and may contribute to the cardioprotective effects of estradiol.
Hypertension 2001 Feb
PMID:Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanism. 1123 Mar 49

Reduced nitric oxide synthesis by glomerular endothelial cells and increased proliferation of glomerular mesangial cells is associated with glomerular remodeling that leads to accelerated glomerulosclerosis. Estradiol induces nitric oxide synthesis and slows the progression of renal disease. Because the estradiol metabolites 2-hydroxyestradiol and 2-methoxyestradiol are more potent than estradiol in inhibiting growth of vascular smooth muscle cells, which are phenotypically similar to mesangial cells, we compared the effects of estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol on growth of glomerular mesangial cells and on basal nitric oxide synthesis by glomerular endothelial cells. In human glomerular mesangial cells, estradiol and its metabolites concentration-dependently (1 nmol/L to 10 micromol/L) inhibited serum (2.5%)-induced DNA synthesis, cell proliferation, and collagen synthesis with the order of potency being 2-methoxyestradiol > 2-hydroxyestradiol > estradiol. ICI182780 (100 micromol/L, an estrogen receptor antagonist) blocked the growth inhibitory effects of estradiol but not 2-hydroxyestradiol or 2-methoxyestradiol. Treatment with estradiol, but not 2-hydroxyestradiol and 2-methoxyestradiol, induced nitric oxide synthesis (P<0.05, assayed by the formation of (3)H-L-citrulline from (3)H-L-arginine) in human glomerular endothelial cells, and these effects were blocked by ICI182780 and L-NMA (a nitric oxide synthesis inhibitor). In conclusion, estradiol may attenuate glomerulosclerosis by inducing nitric oxide synthesis via an estrogen receptor-dependent mechanism and by conversion to 2-hydroxyestradiol and 2-methoxyestradiol, which inhibit glomerular mesangial cell proliferation independent of estrogen receptors.
Hypertension 2001 Feb
PMID:Effects of estradiol and its metabolites on glomerular endothelial nitric oxide synthesis and mesangial cell growth. 1123 Mar 50

Estradiol may be cardioprotective; however, the mechanisms involved remain unclear. Recent findings that estradiol attenuates neointima formation in estrogen receptor knockout mice suggest that the cardioprotective effects of estradiol may be mediated through estrogen receptor-independent mechanisms. Because 2-methoxyestradiol, an endogenous metabolite of estradiol with no affinity for estrogen receptors, is more potent than estradiol in inhibiting vascular smooth muscle cell growth, it is feasible that 2-methoxyestradiol mediates in part the cardioprotective effects of estradiol. To address this hypothesis, we examined the kinetics of 2-methoxyestradiol synthesis in vascular smooth muscle cells and endothelial cells. In human aortic smooth muscle cells, the V(max), K(m), and V(max)/K(m) ratio values for conversion of 2-hydroxyestradiol to 2-methoxyestradiol were 19+/-0.69 pmol. min(-1) per 10(6) cells, 0.52+/-0.085 micromol/L, and 44+/-4.9 pmol. min(-1). micromol/L per 10(6) cells, respectively. In human coronary artery vascular smooth muscle cells, the V(max), K(m), and V(max)/K(m) ratio values for conversion of 2-hydroxyestradiol to 2-methoxyestradiol were 16+/-0.59 pmol. min(-1) per 10(6) cells, 0.23+/-0.011 micromol/L, and 69+/-3.6 pmol. min(-1). micromol/L per 10(6) cells, respectively (all values significantly different compared with human aortic smooth muscle cells). Also, in human aortic versus coronary artery endothelial cells, the V(max) (33+/-0.24 versus 22+/-0.33 pmol. min(-1) per 10(6) cells, respectively), K(m) (0.20+/-0.010 versus 0.099+/-0.014 micromol/L, respectively), and V(max)/K:(m) (163+/-7.7 versus 243+/-41 pmol. min(-1). micromol/L per 10(6) cells, respectively) values were significantly different. Our results indicate that vascular smooth muscle and endothelial cells effectively metabolize 2-hydroxyestradiol to 2-methoxyestradiol. The lower K(m) and higher V(max)/K(m) ratio of human coronary versus aortic cells indicate a faster rate of local metabolism of 2-hydroxyestradiol to 2-methoxyestradiol in the coronary circulation at low levels of 2-hydroxyestradiol.
Hypertension 2001 Feb
PMID:Increased 2-methoxyestradiol production in human coronary versus aortic vascular cells. 1123 Mar 52

The SHHF/Mcc-fa(cp) (spontaneous hypertension and heart failure) rat is advanced as a novel and suitable non-primate model of pregnancy-associated hypertension and fetal growth restriction because it simultaneously has spontaneous pregnancy-associated hypertension, small for gestational age (SGA) offsprings, and altered placental gene expression. Pregnancy-associated hypertension is a major contributor to maternal and fetal morbidity and mortality with the potential to result in maternal death and the need for iatrogenic preterm delivery. It has been reported to develop spontaneously in humans, but not in animals; consequently, progress in identifying the cause and pathogenesis of this disorder has been hampered. Spontaneous hypertension and heart failure rats develop hypertension spontaneously as they age, therefore we sought to determine whether these rats developed hypertension and SGA offsprings during pregnancy. Our results show that systolic blood pressure (BP) increased >40 mm Hg by the end of the first trimester and remained at this elevated level for the remainder of pregnancy, but decreased after parturition. Placenta weights of SHHF rats (0.60 +/- 0.02 g, n = 36) were significantly higher than Wistar-Kyoto (WKY) rats (0.42 +/- 0.01 g, n = 22, P < .05), but pup weights were significantly lower (2.68 +/- 0.06 g for SHHF rats compared to 3.24 +/- 0.06 g for WKY controls, P < .05). Histologic examination revealed pathologic lesions in neither heart, liver, placenta, nor kidney. L-Arginine administered in drinking water prevented the elevation of BP, particularly during the third trimester. Placentas from SHHF rats displayed altered expression of several genes whose protein products have been implicated in preeclampsia, including serotonin receptor, sodium channel, carbonic anhydrase, estrogen receptor regulator, major histocompatibility complex proteins, superoxide dismutase, and angiotensiogen. In addition, gene expression profiling showed alteration of a number of subcellular putative myristoylproteins not previously associated with preeclampsia, particularly those engaged in post-translational modifications in the placenta. Thus, SHHF rats may be a valuable tool, because it simultaneously has spontaneous pregnancy-associated hypertension, SGA offsprings, and altered placental gene expression.
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PMID:Spontaneous pregnancy-induced hypertension and intrauterine growth restriction in rats. 1171 Jul 86

Estrogen has cardioprotective effects. In addition to beneficial effects on lipid metabolism, estrogen affects the vascular tone and may reduce endothelial dysfunction. In the present study, we examined acute gender-specific hemodynamic and inotropic effects of 17beta-estradiol (17beta-E) versus the control situation in open-chest rats. In addition to measurements in the intact circulation, myocardial function was examined on the basis of isovolumic registration independent of peripheral vascular effects. Regarding the dose-dependent and gender-specific effects of 17beta-E, in female rats, 17beta-E (50, 100, or 200 ng/kg) increased cardiac output (CO) (26%, 43%, and 59% versus control animals) as a result of reduction in total peripheral resistance (TPR) (-13%, -18%, and -24%) without any effect on myocardial contractility (isovolumic left ventricular systolic pressure, -1%, 0%, and -6%). These vascular effects are less pronounced in male rats (for 200 ng/kg 17beta-E: CO, 34%; TPR, -14%). We investigated gender-specific effects of 200 ng/kg 17beta-E after pretreatment with the estrogen receptor (ER) antagonist ICI 182,780. ER blockade reduced the effects of estrogen in female rats (CO, 29%; TPR, -17%) and male rats (CO, 19%; TPR, -11%). Regarding the effects of 200 ng/kg 17beta-E after pretreatment with N(G)-nitro-L-arginine methyl ester, NO synthesis inhibition completely prevented the acute vascular effects of estrogen in female rats (CO, -4%; TPR, 1%). In addition, immunohistochemical staining revealed no gender-specific differences of the vascular ER distribution. 17beta-E caused an acute dose-dependent and gender-specific reduction in the afterload. ERs are involved in both genders in this vasodilative effect that is mediated by NO. This NO-mediated effect may explain in part the cardioprotective effect of estrogen.
Hypertension 2001 Nov
PMID:Acute gender-specific hemodynamic and inotropic effects of 17beta-estradiol on rats. 1171 89

Estradiol inhibits cardiac fibroblast growth and may protect against cardiac remodeling associated with heart disease. However, the mechanisms by which estradiol attenuates cardiac fibroblast growth remain unclear. Because cardiac fibroblasts express cytochrome P450s (CYP450s) and catechol-O-methyltransferase (COMT) capable of converting estradiol to hydroxyestradiols and methoxyestradiols, respectively, and because hydroxyestradiols and methoxyestradiols (estradiol metabolites with little affinity for estrogen receptors) are potent inhibitors of cardiac fibroblast growth, we hypothesized that the antimitogenic effects of estradiol are mediated via hydroxyestradiols and/or methoxyestradiols. The inhibitory effects of estradiol (1 to 100 nmol/L) on serum-stimulated (3)H-thymidine incorporation (DNA synthesis), (3)H-proline incorporation (collagen synthesis), and cell number (proliferation) were enhanced (P<0.005) by CYP450 inducers 3-methylcholanthrene (10 micromol/L) and phenobarbital (10 micromol/L). Moreover, the inhibitory effects of estradiol were blocked by the CYP450 inhibitor 1-aminobenzotriazole (10 micromol/L) and the COMT inhibitors quercetin (10 micromol/L) and OR486 (10 micromol/L). In contrast to estradiol, the modulators of CYP450 and COMT were poor ligands for estrogen receptors (binding affinity less-than-or-equal 0.0001% versus estradiol). In cardiac fibroblasts, both quercetin and OR486 inhibited the metabolism of hydroxyestradiol to methoxyestradiol and blocked the inhibitory effects of hydroxyestradiol on cardiac fibroblast proliferation and DNA and collagen synthesis. The abrogating effects of quercetin and OR486 on the metabolism and antimitogenic effects of 2-hydroxyestradiol were mimicked by 20 micromol/L norepinephrine and isoproterenol, substrates for COMT. Our findings provide evidence that estradiol can inhibit cardiac fibroblast growth via an estrogen receptor--independent pathway that involves the local metabolism of estradiol to methoxyestradiols.
Hypertension 2002 Feb
PMID:Methoxyestradiols mediate the antimitogenic effects of locally applied estradiol on cardiac fibroblast growth. 1188 82

Metabolism of locally applied 17beta-estradiol (estradiol) to methoxyestradiols contributes to the growth inhibiting effects of estradiol on vascular smooth muscle cells via an estrogen receptor (ER)-independent mechanism. Because vascular smooth muscle cells are phenotypically similar to glomerular mesangial cells, it is feasible that estradiol inhibits glomerular mesangial cell growth via a similar mechanism, and this possibility was investigated. In human glomerular mesangail cells, estradiol concentration dependently (1 to 100 nmol/L) inhibited serum-induced proliferation (cell number) and DNA ((3)[H]-thymidine incorporation) and collagen ((3)[H]-proline incorporation) synthesis. The inhibitory effects of estradiol were mimicked by 2-hydroxyestradiol and 2-methoxyestradiol, metabolites of estradiol with little affinity for ERs. 2-Hydroxyestradiol and 2-methoxyestradiol were more potent growth inhibitors than estradiol. The inhibitory effects of estradiol were enhanced by CYP450 inducers 3-methylcholanthrene (10 micromol/L) and phenobarbital (10 micromol/L) and blocked by the CYP450 inhibitor 1-aminobenzotriazole (10 micromol/L). The growth inhibitory effects of estradiol were also blocked by quercetin (10 micromol/L) and OR 486 (10 micromol/L) inhibitors of catechol-O-methyltransferase (converts catecholestradiols to methoxyestradiols). ICI182780 (ER antagonist with ER binding affinity similar to estradiol) blocked the growth inhibitory effects of estradiol (1 to 100 nmol/L) only at concentrations (>50 micromol/L) that inhibited estradiol metabolism to catecholestradiols. The growth inhibitory effects of 2-hydroxyestradiol were abrogated by quercetin and OR486 (two structurally dissimilar catechol-O-methyltransferase inhibitors), but not by ICI182780. However, the growth inhibitory effects of 2-methoxyestradiol were unaltered by catechol-O-methyltransferase inhibitors and ICI182780. In conclusion, our findings provide the first evidence that methoxyestradiols mediate the growth inhibitory effects of locally applied estradiol on glomerular mesangial cell growth via an ER-independent mechanism.
Hypertension 2002 Feb
PMID:Role of methoxyestradiols in the growth inhibitory effects of estradiol on human glomerular mesangial cells. 1188 83

Hypertension is more common in men and postmenopausal women than in premenopausal women, and gender differences in sensitivity to high dietary Na(+) salt have been suggested; however, the vascular mechanisms involved are unclear. We investigated whether increases in the extracellular concentration of Na(+) ([Na(+)](e)) enhance the mechanisms of vascular smooth muscle contraction and whether the vascular effects of [Na(+)](e) exhibit gender differences. Isometric contraction and (45)Ca(2+) influx were measured in endothelium-denuded aortic strips that were isolated from intact male, intact female, castrated male, and ovariectomized (OVX) female Sprague-Dawley rats and incubated in Krebs' solution (2.5 mmol/L Ca(2+)) containing increasing [Na(+)](e) by the addition of 1, 3, 6, 10, 20, and 30 mmol/L NaCl. Increasing [Na(+)](e) for 30 minutes did not increase the resting tone or (45)Ca(2+) influx in any group of rats. Phenylephrine (Phe) caused concentration-dependent increases in contraction and (45)Ca(2+) influx. In vascular strips from intact males, increasing [Na(+)](e) by the addition of 1 to 6 mmol/L NaCl significantly increased the magnitude of Phe contraction and (45)Ca(2+) influx. Further increases in [Na(+)](e) by the addition of 10, 20, and 30 mmol/L NaCl increased Phe-induced (45)Ca(2+) influx but inhibited Phe contraction, possibly because of excessive increases in ionic strength. Preincubation with 2,4-dichlorobenzamil (10(-5) mol/L), inhibitor of the Na(+)-Ca(2+) exchanger, or KB-R7943 (10(-5) mol/L), selective inhibitor of the reverse mode of the Na(+)-Ca(2+) exchanger, abolished the increases in Phe contraction and (45)Ca(2+) influx at increasing [Na(+)](e) obtained by the addition of 1 to 6 mmol/L NaCl. Preincubation in Krebs' solution containing control [Na(+)](e) plus 1 to 6 mmol/L LiCl or N-methyl-D-glucamine did not increase Phe contraction. In intact females, the Phe contraction and Ca(2+) influx were less than those in intact males and were not enhanced with increases in [Na(+)](e). The enhancement of Phe contraction and Ca(2+) influx with increases in [Na(+)](e) were not significantly different between castrated male rats and intact male rats but were greater in OVX female rats than intact female rats. In OVX female rats or castrated male rats treated with 17beta-estradiol (but not 17alpha-estradiol) subcutaneous implants, no significant changes in Phe contraction or Ca(2+) influx with increases in [Na(+)](e) were observed. In OVX female or castrated male rats simultaneously treated with 17beta-estradiol plus the estrogen receptor antagonist ICI 182,780, the Phe contraction and Ca(2+) influx were enhanced with increases in [Na(+)](e). Thus, in intact male rats, small physiological increases in [Na(+)](e) enhance smooth muscle contraction to Phe by a mechanism involving Ca(2+) entry, possibly via the reverse mode of the Na(+)-Ca(2+) exchanger. This mechanism appears to be reduced in the presence of endogenous or exogenous estrogen and thereby protects female rats against excessive increases in vascular reactivity during high dietary Na(+) intake.
Hypertension 2002 Feb
PMID:Gender differences in vascular smooth muscle reactivity to increases in extracellular sodium salt. 1188 84


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