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      Vasomotor action of androgens in the mesenteric artery of hypertensive rats. Role of perivascular innervation

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          Abstract

          Androgens may exert cardiovascular protective actions by regulating the release and function of different vascular factors. In addition, testosterone (TES) and its 5-reduced metabolites, 5α- and 5β-dihydrotestosterone (5α- and 5β-DHT) induce vasorelaxant and hypotensive effects. Furthermore, hypertension has been reported to alter the release and function of the neurotransmitters nitric oxide (NO), calcitonin gene-related peptide (CGRP) and noradrenaline (NA). Since the mesenteric arteries possess a dense perivascular innervation and significantly regulate total peripheral vascular resistance, the objective of this study was to analyze the effect of TES, 5α- and 5β-DHT on the neurogenic release and vasomotor function of NO, CGRP and NA. For this purpose, the superior mesenteric artery from male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats was used to analyze: (i) the effect of androgens (10 nM, incubated for 30 min) on the neurogenic release of NO, CGRP and NA and (ii) the vasoconstrictor-response to NA and the vasodilator responses to the NO donor, sodium nitroprusside (SNP) and exogenous CGRP. The results showed that TES, 5α- or 5β-DHT did not modify the release of NO, CGRP or NA induced by electrical field stimulation (EFS) in the arteries of SHR; however, in the arteries of WKY rats androgens only caused an increase in EFS-induced NO release. Moreover, TES, and especially 5β-DHT, increased the vasodilator response induced by SNP and CGRP in the arteries of SHR. These findings could be contributing to the hypotensive/antihypertensive efficacy of 5β-DHT previously described in conscious SHR and WKY rats, pointing to 5β- DHT as a potential drug for the treatment of hypertension.

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          Most cited references71

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          Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men.

          There is a significant uncertainty regarding the effect of testosterone replacement therapy (TRT) on cardiovascular (CV) outcomes including myocardial infarction (MI) and stroke. The aim of this study was to examine the relationship between normalization of total testosterone (TT) after TRT and CV events as well as all-cause mortality in patients without previous history of MI and stroke.
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            Testosterone: a vascular hormone in health and disease.

            Coronary heart disease is a leading cause of premature death in men. Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease (CVD). Furthermore, a low testosterone level is associated in some but not in all observational studies with an increase in cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation: key mediators of atherosclerosis. A bidirectional relationship between low endogenous testosterone levels and concurrent illness complicates attempts to validate causality in this association and potential mechanistic actions are complex. Testosterone is a vasoactive hormone that predominantly has vasodilatory actions on several vascular beds, although some studies have reported conflicting effects. In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure. Although the mechanism of the action of testosterone on vascular tone in vivo is not understood, laboratory research has found that testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells. Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis. The translational effects of testosterone between in vitro animal and human studies, some of which have conflicting effects, will be discussed in this review. We review the evidence for a role of testosterone in vascular health, its therapeutic potential and safety in hypogonadal men with CVD, and some of the possible underlying mechanisms.
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              Testosterone therapy and cardiovascular risk: advances and controversies.

              Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.
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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: Writing – original draft
                Role: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2 February 2021
                2021
                : 16
                : 2
                : e0246254
                Affiliations
                [1 ] Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Spain
                [2 ] Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain
                Max Delbruck Centrum fur Molekulare Medizin Berlin Buch, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-4670-7146
                Article
                PONE-D-20-29895
                10.1371/journal.pone.0246254
                7853503
                33529222
                c4ec4917-b873-4e31-9c2f-c6582a143141
                © 2021 Isidoro-García et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 September 2020
                : 18 January 2021
                Page count
                Figures: 4, Tables: 1, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: PI19/01282
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100012818, Comunidad de Madrid;
                Award ID: S2013/ABI-2783, “INSPIRA1-CM”
                Award Recipient :
                Funded by: Fondo Europeo de Desarrollo Regional
                Award Recipient :
                This study was supported by grants to MF from the Instituto de Salud Carlos III (PI11/00406 and PI19/01282), Comunidad de Madrid (S2013/ABI-2783, “INSPIRA1- CM”) and Fondo Europeo de Desarrollo Regional. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Hormones
                Androgens
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Blood Vessels
                Arteries
                Mesenteric Arteries
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Blood Vessels
                Arteries
                Mesenteric Arteries
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Blood Vessels
                Arteries
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Blood Vessels
                Arteries
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurotransmitters
                Biology and Life Sciences
                Neuroscience
                Neurochemistry
                Neurotransmitters
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Hypertension
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurochemicals
                Nitric Oxide
                Biology and Life Sciences
                Neuroscience
                Neurochemistry
                Neurochemicals
                Nitric Oxide
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Vasodilators
                Biology and Life Sciences
                Biochemistry
                Hormones
                Androgens
                Testosterone
                Biology and Life Sciences
                Biochemistry
                Hormones
                Lipid Hormones
                Testosterone
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                All relevant data are within the manuscript and its Supporting Information files.

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