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      Male Castration Increases Neuronal Nitric Oxide Synthase Activity in the Rat Mesenteric Artery through Protein Kinase C Activation

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          The objective of the present study was to assess the effect of endogenous male sex hormones on the activity of protein kinase C (PKC), as well as the regulatory effect of this kinase on the neuronal nitric oxide (NO) release induced by electrical field stimulation (EFS; 200 mA; 0.3 ms; 1–16 Hz). For this purpose, superior mesenteric arteries from control and orchidectomized male Sprague-Dawley rats were used. PKC activity was greater in arteries from orchidectomized than control rats. Basal and EFS-induced NO release was similar in arteries from both groups despite the lower nNOS expression in arteries from orchidectomized rats. Phorbol 12,13-dibutyrate (PDBu), a PKC activator, EFS-induced NO release was higher in arteries from control compared to orchidectomized rats. Calphostin C, a non-selective PKC inhibitor, or Gö6976, a PKC inhibitor partially selective for conventional isoforms,abolished the EFS-induced NO release in arteries from control animals, while it was decreased in arteries from orchidectomized animals. The PKCζ pseudosubstrate inhibitor decreased EFS-induced NO release equally in both groups. The NO synthase (NOS) inhibitor Nω-nitro- L-arginine-methyl ester (L-NAME) enhanced the EFS-elicited contractions in arteries from both groups. Calphostin C increased the contractions elicited by EFS in arteries from control and orchidectomized rats. This increase was further enhanced by calphostin C plus L-NAME only in orchidectomized rats. PDBu reduced EFS-induced contraction in arteries from controls but did not affect it in orchidectomized rats. The further addition of L-NAME increased the responses in both types of arteries. These results show that PKC activity is enhanced in mesenteric arteries from orchidectomized rats, which may be the responsible for the greater nNOS activity in these arteries. Conventional and atypical PKCζ isoforms positively regulate nNOS activity in arteries from both control and orchidectomized rats, but the contribution of conventional PKC isoforms to enhanced nNOS activity seems to be greater in arteries from orchidectomized rats.

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          Most cited references 36

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          Specificity and mechanism of action of some commonly used protein kinase inhibitors.

          The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.
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            The role of protein kinase C in cell surface signal transduction and tumour promotion

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              Androgens and cardiovascular disease.

              Globally, cardiovascular disease will continue causing most human deaths for the foreseeable future. The consistent gender gap in life span of approximately 5.6 yr in all advanced economies must derive from gender differences in age-specific cardiovascular death rates, which rise steeply in parallel for both genders but 5-10 yr earlier in men. The lack of inflection point at modal age of menopause, contrasting with unequivocally estrogen-dependent biological markers like breast cancer or bone density, makes estrogen protection of premenopausal women an unlikely explanation. Limited human data suggest that testosterone exposure does not shorten life span in either gender, and oral estrogen treatment increases risk of cardiovascular death in men as it does in women. Alternatively, androgen exposure in early life (perinatal androgen imprinting) may predispose males to earlier onset of atherosclerosis. Following the recent reevaluation of the estrogen-protection orthodoxy, empirical research has flourished into the role of androgens in the progression of cardiovascular disease, highlighting the need to better understand androgen receptor (AR) coregulators, nongenomic androgen effects, tissue-specific metabolic activation of androgens, and androgen sensitivity. Novel therapeutic targets may arise from understanding how androgens enhance early plaque formation and cause vasodilatation via nongenomic androgen effects on vascular smooth muscle, and how tissue-specific variations in androgen effects are modulated by AR coregulators as well as metabolic activation of testosterone to amplify (via 5alpha-reductase to form dihydrotestosterone acting on AR) or diversify (via aromatization to estradiol acting upon estrogen receptor alpha/beta) the biological effects of testosterone on the vasculature. Observational studies show that blood testosterone concentrations are consistently lower among men with cardiovascular disease, suggesting a possible preventive role for testosterone therapy, which requires critical evaluation by further prospective studies. Short-term interventional studies show that testosterone produces a modest but consistent improvement in cardiac ischemia over placebo, comparable to the effects of existing antianginal drugs. By contrast, testosterone therapy has no beneficial effects in peripheral arterial disease but has not been evaluated in cerebrovascular disease. Erectile dysfunction is most frequently caused by pelvic arterial insufficiency due to atherosclerosis, and its sentinel relationship to generalized atherosclerosis is insufficiently appreciated. The commonality of risk factor patterns and mechanisms (including endothelial dysfunction) suggests that the efficacy of antiatherogenic therapy is an important challenge with the potential to enhance men's motivation for prevention and treatment of cardiovascular diseases.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2005
                20 October 2005
                : 42
                : 6
                : 526-534
                Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
                88342 J Vasc Res 2005;42:526–534
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 7, References: 49, Pages: 9
                Research Paper


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