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rosaliesolano7

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In contrast, the A-ring bends 90° relative to the steroid nucleus when the C5 hydrogen is β/cis oriented, as in the case of 5β-reduced androgens such as 5β-DHT (see structural conformations in Fig. 2). We have observed that the A-ring of the steroid nucleus is planar in the structure of Tes and in the α/trans configuration at C5 of reduced metabolites such as 5α-DHT. Nevertheless, the dramatic difference in vasorelaxing potency between Tes and its dihydro-metabolites deserves further consideration, based on their different structural conformations. However, to our knowledge, there is no information available on the plasma concentrations of 5β-DHT; consequently, further research is urgently needed to determine the range of normal plasma concentrations of 5β-DHT. Whereas the circulating plasma concentration of Tes in adult men ranges 11–36 nmol/l, its 5α-reduced metabolite (5α-DHT) is present in the plasma at levels of only about 10% that of Tes (1.0–2.9 nmol/l). As a nonaromatizable dihydro-androgen metabolite of Tes, 5α-DHT has been frequently used as a tool to verify that the aromatization of Tes to estrogen is not required for this androgen to produce vasorelaxation (3, 8, 10, 64, 73).
Gupta et al25 examined the differentiation and proliferation of human mesenchymal stem cells (hMSCs) and preadipocytes in vitro in the presence of DHT. Testosterone supplementation reduced visceral fat accumulation, improved fasting glucose levels, glucose tolerance, and mean arterial pressure, while having no statistically significant impact on total cholesterol or triglyceride levels. These experimental rabbits were compared with control rabbits given a standard diet. Jones et al22 extracted the coronary arteries and thoracic aortas from male rats and placed them in a physiological buffer. Endothelial denudation and l‐NAME treatment had no effect on this result.18 This finding is directly supported by a study done by Tep‐areenan et al19 in rat arteries.
Testosterone's beneficial effect on cell death was mitigated by 5‐hydroxydecanoate, a mitochondrial KATP channel inhibitor, although 5‐HD treatment alone had no effect on cell death compared with the control. To simulate ischemia, cardiomyocytes were centrifuged into a pellet and had mineral oil applied to prevent gas exchange for 60 minutes. To accomplish this, Er and coworkers isolated ventricular cardiomyocytes from rats. Ventricular myocytes were examined in vitro using whole‐cell voltage and current clamps. Thus, expanded research efforts are needed to adequately address both the clinical and biological complexity of the relationship between androgens and CVD. In summary, the interaction between circulating androgens and HDL particles is likely quite complex and remains poorly understood. However, this was a small study and there is a need to verify the findings and better understand the functional implications of the observed changes in HDL constituent proteins .
Conversely, in women, testosterone may augment existing hypertension, increase risk for cardiovascular events, or promote atherogenesis. Two recent observational studies reported increased CV risks in men who received testosterone prescriptions.17,18 Although they gained a significant amount of media attention, neither study provided credible evidence of increased CV risk. Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease (CVD). This study showed that testosterone supplementation may reduce the MetS phenotype, thereby reducing the risk for cardiovascular disease.24
Pham et al tested dofetilide, an antiarrhythmic agent that also may have proarrhythmic properties, against varying levels of testosterone in ventricular myocytes.5 The concentration of testosterone was measured against 90% action potential duration (APD90) and percent incidence of early after depolarizations (EADs). Thus, despite numerous research efforts to date, the role of hypogonadism in the pathogenesis of CVD remains unclear, as does the cardiovascular risk profile of TRT. This raises the possibility that these reductions in HDL-c do not confer increased CVD risk at all and conceivably could reflect a protective effect.
Male rabbits were given a weekly intramuscular injection of testosterone (25 mg/kg) or no treatment. Results of this study showed that treatment with DHT caused upregulation of 27 proatherosclerotic genes in macrophages from male donors, with negative functional consequences. Ng et al39 examined the effect of DHT on human macrophages from both male and female donors in a similar study. There were significantly fewer lesions in the testes‐intact group and the orchiectomy plus testosterone group than in the testes‐intact plus aromatase inhibitor group, the orchiectomized plus placebo group, and the orchiectomized plus testosterone plus aromatase inhibitor group, suggesting that testosterone and aromatase are both necessary for attenuating atherosclerosis.
Although VOCC function may differ in cultured cell lines, the results in primary cultured and freshly dissociated rat aortic myocytes (41) are consistent with the findings of these reports. This possibility is supported by previous in vivo studies that demonstrated that Tes-induced vasodilation of both canine coronary and porcine systemic arteries was nitric oxide (NO) dependent (3, 39). Clearly, these data suggest the presence of an endothelium-dependent mechanism at physiological concentrations of Tes (11–36 nmol/l). In this latter study, sensitivity to Tes-induced vasodilation was much higher in endothelium-intact than in endothelium-denuded vessels (1 nM vs. 30 μM; Ref. 55). Moreover, in electrophysiological (patch clamp) experiments measuring ion currents in single VSM cells, Tes acts at nanomolar concentrations (8, 17, 41, 58, 59) and even at circulating (36 nmol/l) concentrations (17, 58, 59) to inhibit Ca2+ channels.
Second, the modulation of intracellular cAMP by Tes may occur via the sex hormone-binding globulin-Tes complex and may be biologically active via its binding to cell-surface sex hormone-binding globulin receptors that evoke an increase in intracellular cAMP. First, in VSM cells, Tes stimulates NO production (via neuronal NOS), which in turn evokes the formation of cGMP (via guanylyl cyclase) to induce vasorelaxation (8, 68). Moreover, Tes may also cause vasorelaxation by modulating intracellular signal transduction pathways such as increasing the levels of cGMP (8) and cAMP (41), which may indeed evoke vasorelaxation. In porcine coronary myocytes, 200 nM Tes very dramatically activated BKCa channels, increasing the open probability by more than 10-fold (8). Furthermore, the authors (41) presented data revealing that the vasodilatory action of the 5β-reduced metabolite of Tes, 5β-DHT, involves the inhibition of VOCCs from nanomolar to micromolar concentrations (100 nM–32 μM).
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