Gender has an important influence on blood pressure, with premenopausal women having a lower arterial blood pressure than age-matched men. Compared with premenopausal women, postmenopausal women have higher blood pressures, suggesting that ovarian hormones may modulate blood pressure. However, whether sex hormones are responsible for the observed gender-associated differences in arterial blood pressure and whether ovarian hormones account for differences in blood pressure in premenopausal versus postmenopausal women remains unclear. In this review, we provide a discussion of the potential blood pressure regulating effects of female and male sex hormones, as well as the cellular, biochemical and molecular mechanisms by which sex hormones may modify the effects of hypertension on the cardiovascular system.

A number of cellular and biochemical processes are involved in the pathophysiology of glomerular and vascular remodeling, leading to renal and vascular disorders, respectively. Although estradiol protects the renal and cardiovascular systems, the mechanisms involved remain unclear. In this review we provide a discussion of the cellular, biochemical, and molecular mechanisms by which estradiol may exert protective effects on the kidneys and vascular wall. In this regard, we consider the possible role of genomic vs. nongenomic mechanisms and estrogen receptor-dependent vs. estrogen receptor-independent mechanisms in mediating the protective effects of estradiol on the renal and cardiovascular systems.

Nitric oxide (NO) and angiotensin II (All) can effect vascular smooth muscle cell (SMC) proliferation. However, the effects of such agents on SMC migration, an equally important phenomenon with regard to vascular pathophysiology, have received little attention. The objectives of the present study were: (a) to determine whether NO inhibits Allinduced migration of vascular SMCs; (b) to investigate the mechanism of the interaction of NO and All on SMC migration; and (c) to evaluate the All receptor subtype that mediates All-induced SMC migration. Migration of rat SMCs was evaluated using a modified Boydens Chamber (transwell inserts with gelatin-coated polycarbonate membranes, 8 gm pore size). AU stimulated SMC migration in a concentration-dependent manner, and this effect was inhibited by sodium nitroprusside (SNP) and S-nitroso-Nacetylpenicillamine (SNAP). In the presence of L-arginine, but not D-arginine, IL-1p, an inducer of inducible NO synthase, also inhibited AU-induced SMC migration, and this effect was prevented by the NO-synthase inhibitor, N-nitro-L-arglnine methyl ester. The effects of NO donors on AUinduced SMC migration were mimicked by 8-bromo-cGMP. Also, the antimigratory effects of SNAP were partially inhibited by LY83583 (an inhibitor of soluble guanylyl cyclase) and by KT5823 (an inhibitor of cGMP-dependent protein kinase). Although 8-bromo-cAMP (cAMP) also mimicked the antimigratory effects of NO donors, the antimigratory effects of SNAP were not altered by 2',5 '-dideoxyadenosine (an inhibitor of adenyl cyclase) or by (R)-p-adenosine-3 ',5'-cyclic phosphorothioate (an inhibitor of the cAMPdependent protein kinase). type AT2-receptor antagonist CGP 42112, blocked All-induced SMC migration. These findings indicate that (a) NO inhibits AU-induced migration of vascular SMCs; (b) the antimigratory effect of NO is mediated in part via a cGMPdependent mechanism; and (c) All stimulates SMC migration via an AT, receptor. (J. Clin. Invest. 1995. 96:141-149.)

Premenopausal women have a lower risk for cardiovascular events, and mortality due to coronary vascular disease (CVD) in premenopausal women is rare. These facts suggest that endogenous estrogens, such as estradiol, protect the cardiovascular system, and several observational studies and a few small clinical studies conducted in healthy and younger postmenopausal women support this hypothesis. In contrast, two large randomized clinical trials (RCTs), using conjugated equine estrogens and conducted in older women with established CVD or without overt CVD, failed to demonstrate protection against CVD by exogenous estrogens. These divergent findings have resulted in confusion with regard to the association between estrogen deficiency and CVD in postmenopausal women. In order to reconcile these contradictory findings, it is necessary to examine the pathophysiology associated with age-dependent changes within the vessel wall and to compare the pharmacology of different types of estrogens. Understanding age-dependent changes in vascular pathology and the pharmacology of different estrogens may facilitate the development of therapeutic strategies for hormone replacement therapy (HRT) that would be effective in delaying vascular remodeling leading to CVD following menopause. In this review we provide an overview of the impact of menopause and estrogen deficiency on vascular remodeling and emphasize the importance of timing and type of estrogen to achieve maximum benefits with regard to reducing the risk of CVD.

Cardiac fibroblasts synthesize adenosine, and exogenous and cardiac fibroblast-derived adenosine inhibits cardiac fibroblast proliferation via activation of A2B receptors. Cardiac fibroblast-derived adenosine may regulate cardiac hypertrophy and/or remodeling by modulating cardiac fibroblast proliferation.

Endogenous nitric oxide (NO) is an important functional mediator in several physiological systems, including the reproductive system. However, when generated in excessive amounts for long periods, mainly during immunological reactions, NO is cytotoxic and cytostatic for invading microbes, as well as for the cells generating it and the tissues present around it. Since infertility associated with urogenital tract infection in males and females is also accompanied by reduced sperm motility and viability, it is possible that reduced fertility in these patients is due to NO-induced sperm toxicity. We therefore evaluated the direct effects of NO, chemically derived from S-nitroso-A'-acetylpenicillamine (SNAP, 0.012-0.6 mM) and sodium nitroprusside (SNP, 0.25-2.5 mM), on the motility and viability of human spermatozoa. Furthermore, we tested whether inhibition of NO synthesis prevents sperm motility and viability by incubating washed total cells present in the semen (spermatozoa, round cells) with /V-nitro-Larginine-methyl-ester (L-NAME), a NO synthesis inhibitor. Treatment of purified spermatozoa with SNAP or SNP decreased forward progressive sperm motility and straight line velocity, and also increased the percentage of immotile spermatozoa in a concentration-dependent manner. Furthermore, the percentage of immotile spermatozoa positively correlated with the percentage of dead spermatozoa. In contrast to freshly prepared SNAP, SNAP preincubated for 48 h had no effect on the motility and viability of the spermatozoa. Furthermore, as compared to untreated controls, a significantly higher percentage of forward progressive sperm motility as well as viability (P < 0.05) was maintained in washed semen incubated with L-NAME (0.15 mM). Seminal plasma concentrations of nitrite-nitrate (stabile metabolites of NO)/10 6 spermatozoa correlated positively (P < 0.05) with the percentage of immotile spermatozoa. Our results suggest that NO can cause sperm toxicity as well as inhibit sperm motility. In conclusion, excessive NO synthesis in response to infection and inflammation could be an important factor contributing to functional change of the spermatozoa, leading to their dysfunction and to infertility.

A discussion of the role of endogenous estradiol metabolites in mediating important biological actions of estradiol is essentially nonexistent in standard textbooks of pharmacology and endocrinology. Indeed, the prevailing view is that all biological effects of estradiol are initiated by binding of estradiol per se to estrogen receptors and that estradiol metabolites are more or less irrelevant. This orthodox view, which is most likely incorrect, is the fundamental premise (an estrogen is an estrogen is an estrogen) underlying the design of important clinical trials such as the Heart and Estrogen/Progestin Replacement Study and the Women's Health Initiative Study. Accumulating data provide convincing evidence that some metabolites of estradiol, the major estrogen secreted by human ovaries, are biologically active and mediate multiple effects on the cardiovascular and renal systems that are largely independent of estrogen receptors. More specifically, metabolites of estradiol, particularly catecholestradiols and methoxyestradiols, induce multiple estrogen receptor-independent actions that protect the heart, blood vessels, and kidneys from disease. These protective effects are mediated in part by the inhibition of the ability of vascular smooth muscle cells, cardiac fibroblasts, and glomerular mesangial cells to migrate, proliferate, and secrete extracellular matrix proteins, as well as by an improvement in vascular endothelial cell function. The purpose of this review is to highlight the cardiovascular and renal pharmacology of catecholestradiols and methoxyestradiols. The take home message is simple: that when it comes to cardiovascular and renal protection, the concept that all estrogenic compounds are created equal may not be true.The focus of this review is to summarize recent evidence supporting an important role for estradiol metabolites, specifically catecholestradiols and methoxyestradiols, in protecting against cardiovascular and renal diseases.Estradiol Synthesis (Fig. 1) Human beings make three estrogenic steroids, namely estradiol, estriol, and estrone. Of these, estradiol is the most important and estriol and estrone contribute only marginally to the total estrogenic activity in premenopausal women. The biosynthetic pathways leading to estradiol are well described: Aromatase converts androstenedione to estrone, and 17␤-hydroxysteroid dehydrogenase converts estrone to estradiol. In addition, aromatase can also metabolize testosterone directly to estradiol. In premenopausal women, circulating estradiol is synthesized mostly in steroidogenic cells and tissues such as ovarian granulosa cells and placenta. However, several other organs and tissues make estradiol including adipose tissue, skin, endometrium, vaginal mucosa, breast, liver, blood vessels, and heart (Zhu and Conney, 1998; Dubey and Jackson, 2001a,b). Enzymes responsible for estradiol synthesis are also expressed in vascular smooth muscle cells and endothelial cells (Harada et al., 1999) and in cardiac fibroblasts and myocytes (Park 20...

Postmenopausal women (PMW) have an increased risk of cardiovascular disease that is attenuated by hormone replacement therapy (HRT). Inasmuch as hypertension and atherosclerosis are associated with diminished endothelium-derived nitric oxide (NO), we investigated whether HRT augments NO release in PMW. We determined serum levels of nitrite/nitrate (NO2 + NO3) at baseline and during the 6th, 12th, and 24th months of the study in two groups of PMW. One group (HRT-PMW, n = 13) received continuous transdermal administration of 17 beta-estradiol (Estraderm-TTS-50) supplemented with oral norethisterone acetate (NETA) on days 1 through 12 of each month, and the other group (control PMW, n = 13) did not receive HRT. Blood samples in the HRT-PMW group were collected without regard to whether subjects were taking NETA at the time of blood sampling. Serum NO2 + NO3 levels increased in HRT-PMW for the duration of the study, whereas serum NO2 + NO3 levels remained unchanged in control PMW. When all samples regardless of timing of collection with respect to NETA treatment were included in the statistical analysis, the change in NO2 + NO3 levels in HRT-PMW was significantly greater compared with the change in control PMW (P = .037). Likewise, when only those samples collected when estradiol-treated subjects were not taking oral NETA were included in the statistical analysis, the change in NO2 + NO3 levels in the HRT-PMW group remained significant (P = .047) compared with control PMW.(ABSTRACT TRUNCATED AT 250 WORDS)