Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article examines the effect of dose level of both estrogens and progestins as factors in the cardiovascular risk of oral contraceptives (OCs), and also examines the roles of blood pressure, coagulation factors, and lipid metabolism. A large number of epidemiologic studies have demonstrated the connection between OC use and thromboembolic disease since the 1st such study appeared 2 decades ago, but the early studies concerned formulations with much higher estrogen doses than those currently used, taken by women who were older and more likely to smoke than at present. Very few epidemiologic studies dealing with the newer formulations are yet available. It is easier to analyze the dose-response relations for the progestins than for the estrogens given that the 2 estrogens primarily used, ethinyl estradiol (EE) and mestranol, were used for a series of progestins at different doses to examine their effects with a constant dose of estrogen. Nevertheless, the epidemiologic studies show increased risks of thrombotic accidents and a dose-response relation for both the estrogen and progestin components. It is likely that different mechanisms are responsible. The effects of OCs on blood pressure have been monitored carefully since the 1st observations of hypertension in OC users. Blood pressure elevations are usually attributed to the estrogen, but there is evidence of a progestin role as well. Some studies have found differences in blood pressure at the same estrogen dose but with different progestin content. It is very likely that blood pressure undergoes physiologic variations depending on hormonal fluctuations. The mechanism by which some OC users develop hypertension is poorly understood, but it may be related to changes in the renin-angiotensin-aldosterone system. Androgenic progestins accentuate sodium retention, which may play a role. Researchers have shown that the lipid profiles of women at different stages of life are different, whether or not they use OCs. Among young women HDL cholesterol levels decline and LDL levels increase among users relative to nonusers of OCs. On the other hand, old women receiving estrogen substitution therapy tend to have more favorable lipid profiles than do women of the same age not receiving estrogen. Coagulation factors, especially factors VII and fibrinogen, have been established as important cardiovascular risk factors in men. Some studies have shown the levels of factors VII and fibrinogen to be elevated in OC users. These procoagulant alterations are also observed in women receiving estrogen substitution, but unlike OC users such women appear to be protected by age-related increases in the level of antithrombin III. Smoking is an important influence on the fibrinogen level, which probably explains part of the increased risk of myocardial infarct among OC users.
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PMID:[Cardiovascular risks of oral contraceptives: dose-response relationship]. 1234 20

Estrogen produces both beneficial and adverse effects on cardiovascular health via mechanisms that remain unclear. Stroke-prone spontaneously hypertensive rats (SHRSP) maintained on Stroke-Prone Rodent Diet and 1% NaCl drinking water (starting at 8 wk of age) rapidly develop stroke and malignant nephrosclerosis that can be prevented, despite continued hypertension, by drugs targeting angiotensin II and aldosterone actions. This study evaluated estrogen's effects in the SHRSP model. Female SHRSP that were sham operated (SHAM), ovariectomized (OVX) at 4 wk of age, or OVX and treated with estradiol benzoate (E2,30 microg x kg-1 x wk-1) were studied. In a survival protocol, OVX rats lived significantly longer (15.1 +/- 0.3 wk) compared with SHAM (13.6 +/- 0.2 wk) or OVX+E2 rats (12.4 +/- 0.2 wk). In a protocol in which animals were matched for age, at 11.5 wk, terminal systolic blood pressure and urine protein excretion were elevated in SHAM and OVX+E2 rats compared with OVX rats; blood urea nitrogen, renal microvascular and glomerular lesions, and plasma renin concentration were elevated in OVX+E2 relative to SHAM or OVX rats. In a survival protocol using intact female SHRSP, treatment with an antiestrogen (tamoxifen, 7 mg.kg-1.wk-1) prolonged survival by >2 wk compared with controls (P < 0.01). The data indicate that estrogen promotes microangiopathy in the kidney and stroke in saline-drinking SHRSP.
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PMID:Estrogen promotes microvascular pathology in female stroke-prone spontaneously hypertensive rats. 1267 Aug 33

The influence of estrogen on the regulation of cardiovascular function remains a controversial and complex area of investigation. We assessed the effects of estrogen depletion in the congenic mRen(2). Lewis rat, established from the back-cross of the original (mRen2)-27 transgenic onto the Lewis inbred strain. Ovariectomy of heterozygous mRen(2). Lewis at 4 to 5 weeks resulted in a progressive increase in blood pressure compared with the sham surgery congenics at weeks 6 to 11. At 11 weeks, the ovariectomized mRen(2). Lewis (OVX) systolic blood pressure averaged 195+/-3.7 mm Hg versus 141+/-4.0 mm Hg for sham. Plasma Angiotensin (Ang) II, serum ACE activity, plasma renin concentration, as well as urinary excretion of Ang II, 8-isoprostane F2alpha, and endothelin-1 were elevated; however, renal mRNA levels of eNOS were suppressed after ovariectomy. Estrogen replacement reduced blood pressure below both the sham and OVX by 11 weeks (125+/-2.9 mm Hg, n=7, P<0.01 versus OVX and sham). Moreover, the AT1 receptor antagonist olmesartan (CS866; week 12 to 16) essentially normalized blood pressure to 113+/-5.4 mm Hg (n=6, P<0.01 versus OVX and sham). The attenuation of the hypertension was still evident 7 weeks after complete withdrawal of treatment (124+/-4.1 mm Hg at week 23). In summary, the OVX mRen.2. Lewis exhibited a rapid and sustained increase in blood pressure. Estrogen or olmesartan lowered pressure by a similar extent. We conclude that the ovary exerts considerable influence on the regulation of the blood pressure in the mRen2. Lewis strain, possibly by limiting activation of the renin-angiotensin system.
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PMID:Estrogen or the AT1 antagonist olmesartan reverses the development of profound hypertension in the congenic mRen2. Lewis rat. 1287 87

The present study evaluated the importance of ovarian functions and the renin-angiotensin system in the progression of the right ventricular (RV) hypertrophy. Female Sprague-Dawley rats were bilaterally ovariectomized (Ovx) and injected with monocrotaline (MCT, 60 mg/kg, sc). Four weeks after MCT-treatment, only the male and Ovx female rats showed marked RV hypertrophy. The hypertrophied RV of the male-MCT and Ovx-MCT rats exhibited remarkably elevated renin mRNA levels. Gene expression levels of angiotensinogen, TGF-beta1, and endothelin-1 in the hypertrophied RV also increased, but to the less degree than did the renin mRNA. To investigate beneficial effects of estrogen or enalapril on progression of the pulmonary hypertension and RV hypertrophy, histological changes of the lung and heart were examined. Sham-MCT female rats showed histological changes indicating pulmonary hypertension without RV hypertrophy. In contrast, Ovx-MCT rats showed marked RV hypertrophy with pathological changes, denoting severe pulmonary and myocardial injuries. Estrogen-or enalapril-treated Ovx-MCT rats did not show RV hypertrophy, and showed remarkably ameliorated ultrastructural changes in the lung and RV. These results from this rat model suggest that both estrogen and inhibition of the renin-angiotensin system have protective functions against the development of the pulmonary hypertension and cardiac remodeling.
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PMID:Estrogen and enalapril attenuate the development of right ventricular hypertrophy induced by monocrotaline in ovariectomized rats. 1455 14

Progesterone is more than a progestin. Beyond functions in cycle and pregnancy, progesterone binds with high affinity to the mineralocorticoid receptor (MR) acting as an antagonist, with obvious significance for electrolyte homeostasis, an array of MR-related functions in the circulation as well as in the CNS. Progesterone induces natriuresis at physiological concentrations. Lack of antimineralocorticoid activity with conventional progestins may account for sodium and water retention, minor elevation of blood pressure and "pill hypertension" in susceptible women on oral contraceptives. Ethinylestradiol (EE) contributes to this problem by distinct activation of the renin-angiotensin-aldosterone (RAAS) system. Drospirenone (DRSP: 6beta,7beta,15beta,16beta-dimethylene-3-oxo 17alpha-pregn-4-ene-21,17 carbolactone) is the first synthetic progestin with antialdosterone activity. DRSP and progesterone bind to PR in uterine (affinity of both is about 30% of R5020) and MR in kidney cytosol (affinity about 230 and 100% of aldosterone, respectively). Intrauterine administration of DRSP in silastic tubes induced maximum local progestational effects in rabbits. At systemic subcutaneous (s.c.) administration (McPhail-assay) full endometrial transformation was obtained at 1mg per animal per day. At 1-3mg DRSP per animal per day subcutaneously, pregnancy maintenance after ovariectomy, antiovulatory activity, and antimineralocorticoid activity were seen in the respective assays in rats. The latter activity indicates about eight-fold higher potency than spironolactone. DRSP decreased blood pressure in male hypertensive rats, whereas an increase was noted under conventional progestins. DRSP also prevented hypertension and fetal growth retardation in pregnant rats after L-NAME, an inhibitor of nitric oxide synthase. DRSP has antiandrogenic activity. Feminizing effects were recorded during sexual differentiation in male fetuses at high doses. Powerful antiandrogenic effects were also seen in gonad intact and testosterone substituted castrated male rats. The antiandrogenic potency of DRSP is superior to that of spironolactone but below that of cyproterone acetate. Endometrial transformation, inhibition of ovulation, and antimineralocorticoid, i.e. natriuretic effects and mild antiandrogenic effects were recorded at the same range of oral doses (0.5-4 mg per day) in humans. Combined with EE (3 mg DRSP+30 microg EE), DRSP provides effective inhibition of ovulation and cycle control. Body weight compared to conventional oral contraceptives was reduced. DRSP (3 mg per day+15, 20, or 30 microg ethinyl estradiol per day) prevented the mild increase of blood pressure seen under a conventional levonorgestrel-containing contraceptive and even tended to reduce pretreatment blood pressure. Studies on modulation (i.e. inhibition) of glucocorticoid effects at the MR in the CNS remain an unexplored and interesting area for research.
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PMID:Conception and pharmacodynamic profile of drospirenone. 1466 81

Large differences exist between women and men in the syndrome of heart failure (HF). In contrast to men, hypertension and diabetes represent the major risk factors for development of HF in women and hypertension is also the major cause of left ventricular hypertrophy and stroke. Left ventricular hypertrophy in women increases the risk for mortality to a higher degree than it does in men. The clinical course of HF is generally more benign and more frequently characterized by HF with preserved systolic function. Estrogen receptors are present in the human heart. Based on data from rodent models, they are believed to modulate hypertrophy and the progression of HF. Some of the signaling pathways have been described and involve phosphorylation of intracellular kinases and production of nitric oxide. Interestingly, estrogen receptors are upregulated in human hypertrophy and HF. The clinical course of HF in women is characterized by the more frequent occurrence of diastolic HF. Myocardial remodeling with age and, as a consequence, of mechanical load is different in both genders. Adherence to guidelines in the diagnosis and treatment of HF is less strict in women than in men, leading to undertreatment with inhibitors of the renin-angiotensin system. Women are generally underrepresented in clinical trials in HF and gender-specific analyses have been neglected in most older large survival trials. In some of the large survival studies angiotensin-converting enzyme inhibitors or beta-receptor blockers did not reach significant endpoints in women. However, meta-analyses show overall positive effects for these groups of substances. Angiotensin receptor blockers were effective in large studies including high percentages of women.
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PMID:Heart failure and its treatment in women. Role of hypertension, diabetes, and estrogen. 1613 38

Estrogen's suggested cardio-protective effects have come into question following the results of recent clinical trials. Two major components of the renin-angiotensin system (RAS) that are modulated by estrogen are angiotensin converting enzyme, and the angiotensin II type 1 receptor. Further research has revealed several new components of the RAS, including angiotensin converting enzyme 2, its peptide product angiotensin 1-7 (Ang 1-7), and that peptide's receptor, Mas. These components appear to oppose the classical effects of the RAS, and may act to buffer the RAS in vivo. Recent work has shown that during pregnancy, when estradiol levels are elevated, renal and urinary Ang 1-7 are greatly increased. This study examined the effects of estradiol on the efficacy of Ang 1-7 in the rat aorta. Female Sprague-Dawley rats were ovariectomized and a subgroup was chronically treated with subcutaneous pellets of estradiol for 3 weeks. Thoracic aortas were harvested for assessment of in vitro vascular reactivity to Ang 1-7. The results demonstrated that increased estradiol exposure attenuated the relaxation response to Ang 1-7 in a dose-dependent manner. These findings are in contrast to recent work showing potentiated responses to Ang 1-7 in mesenteric arteries from estrogen-manipulated rats, and may suggest a regional specificity in estradiol-mediated changes in the RAS.
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PMID:Alterations in aortic vascular reactivity to angiotensin 1-7 in 17-beta-estradiol-treated female SD rats. 1621 74

Estrogen protects against increases in arterial pressure (AP) by acting on blood vessels and on cardiovascular centers in the brain. The mechanisms underlying the effects of estrogen in the brain stem, however, are not clear. The aim of the present study was to determine whether ovariectomy affects AP via the Rho/Rho-kinase pathway in the brain stem. We performed bilateral ovariectomy in 12-week-old female spontaneously hypertensive rats. AP and heart rate (HR), measured using radiotelemetry in awake rats, were increased in ovariectomized rats compared with control rats (mean AP: 163+/-3 versus 144+/-4 mm Hg; HR: 455+/-4 versus 380+/-6 bpm). Continuous intracisternal infusion of Y-27632 significantly attenuated the ovariectomy-induced increase in AP and HR (mean AP: 137+/-6 versus 163+/-3 mm Hg; HR: 379+/-10 versus 455+/-4 bpm). In addition, we confirmed the increase of Rho-kinase activity in the brain stem in ovariectomized rats, and the increase was attenuated by intracisternal infusion of Y-27632 via the phosphorylated ezrin, radixin, and moesin (ERM) family, which are Rho-kinase target proteins. Furthermore, angiotensin II type 1 receptor expression in the brain stem was significantly greater in ovariectomized rats than in control rats, and the increase was partially reduced by intracisternal infusion of Y-27632. In a separate group of animals, we confirmed that the serum and cerebrospinal fluid 17beta-estradiol concentrations decreased in ovariectomized rats. These results suggest that depletion of endogenous estrogen by ovariectomy, at least in part, induces hypertension in female spontaneously hypertensive rats via activation of the renin-angiotensin system and the Rho/Rho-kinase pathway in the brain stem.
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PMID:Ovariectomy augments hypertension through rho-kinase activation in the brain stem in female spontaneously hypertensive rats. 1694 Feb 29

Estrogen depletion markedly exacerbates hypertension in female congenic mRen2. Lewis rats, a model of tissue renin overexpression. Because estrogen influences nitric oxide synthase (NOS) and NO may exert differential effects on blood pressure, the present study investigated the functional expression of NOS isoforms in the kidney of ovariectomized (OVX) mRen2. Lewis rats. OVX-mRen2. Lewis exhibited an increase in systolic blood pressure (SBP) of 171 +/- 5 vs. 141 +/- 7 mmHg (P < 0.01) for intact littermates. Renal cortical mRNA and protein levels for endothelial NOS (eNOS) were reduced 50-60% (P < 0.05) and negatively correlated with blood pressure. In contrast, cortical neuronal NOS (nNOS) mRNA and protein levels increased 100 to 300% (P < 0.05). In the OVX kidney, nNOS immunostaining was more evident in the macula densa, cortical tubules, and the medullary collecting ducts compared with the intact group. To determine whether the increase in renal nNOS expression constitutes a compensatory response to the reduction in renal eNOS, we treated both intact and OVX mRen2. Lewis rats with the selective nNOS inhibitor L-VNIO from 11 to 15 wk of age. The nNOS inhibitor reduced blood pressure in the OVX group (185 +/- 3 vs. 151 +/- 8 mmHg, P < 0.05), but pressure was not altered in the intact group (146 +/- 4 vs. 151 +/- 4 mmHg). In summary, exacerbation of blood pressure in the OVX mRen2. Lewis rats was associated with the discoordinate regulation of renal NOS isoforms. Estrogen sensitivity in this congenic strain may involve the influence of NO through the regulation of both eNOS and nNOS.
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PMID:Discoordinate regulation of renal nitric oxide synthase isoforms in ovariectomized mRen2. Lewis rats. 1702 69

Heart failure with normal ejection fraction (HF-NEF) is frequently believed to be more common in women than in men. However, the interaction of gender and age has rarely been analyzed in detail, and knowledge of the distinction between pre- and postmenopausal women is lacking. Some of the studies that have described a higher prevalence of HF-NEF in women relied on clinical diagnoses of HF together with normal systolic function and did not measure diastolic function. This applies to the analysis of patients hospitalized for HF and some epidemiological investigations that agree on the greater prevalence of HF-NEF in women. Population-based studies with echocardiographic determination of diastolic function have suggested equal or greater prevalence of diastolic dysfunction in men. Major risk factors for HF-NEF include hypertension, aging, obesity, diabetes, and ischemia. Hypertension is more frequent in women and can contribute to left ventricular and arterial stiffening in a gender-specific way. Aging, obesity, and diabetes affect myocardial and vascular stiffness differently and lead to different forms of myocardial hypertrophy in women and men. In contrast, ischemia may play a greater role in men. Gender differences in ventricular diastolic distensibility, in vascular stiffness and ventricular/vascular coupling, in skeletal muscle adaptation to HF, and in the perception of symptoms may contribute to a greater rate of HF-NEF in women. The underlying molecular mechanisms include gender differences in calcium handling, in the NO system, and in natriuretic peptides. Estrogen affects collagen synthesis and degradation and inhibits the renin-angiotensin system. Effects of estrogen may provide benefit to premenopausal women, and the loss of its protective mechanisms may render the heart of postmenopausal women more vulnerable. Thus, a number of molecular mechanisms can contribute to the gender differences in HF-NEF.
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PMID:Role of gender in heart failure with normal left ventricular ejection fraction. 1718 12


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