Testosterone relaxes coronary arteries by opening the large-conductance, calcium-activated potassium channel

Abstract

Cardiovascular diseases are often considered to be a predominantly male health problem, and it has been suggested that testosterone exerts deleterious effects on cardiovascular function; however, few experimental studies support this suggestion. Moreover, the cellular and molecular mechanism(s) underlying vascular responses to testosterone is unknown. The present study has investigated the acute effects of testosterone on porcine coronary artery smooth muscle at the tissue and cellular levels. Contractile studies demonstrated that testosterone or dihydrotestosterone (a nonaromatizable metabolite) relaxed these arteries by an endothelium-independent mechanism involving potassium efflux. Direct evidence from patch-clamp studies confirmed that testosterone opened K(+) channels in single coronary myocytes, and further analysis identified this protein as the large-conductance, calcium- and voltage-activated potassium (BK(Ca)) channel. Moreover, inhibiting BK(Ca) channel activity significantly attenuated testosterone-induced coronary relaxation. These findings indicate that testosterone relaxes porcine coronary arteries predominantly by opening BK(Ca) channels in coronary myocytes, and this response may be associated with accumulation of cGMP. This novel mechanism may provide a better understanding of testosterone-induced vasorelaxation reported in recent experimental and early clinical studies.

The effects of testosterone on isolated sheep coronary artery

“…Our results do not agree with those from previous studies which have utilized other in vivo and in vitro animal models to demonstrate that the vasodilatory action of testosterone is not solely reliant upon the presence of intact endothelial cell layer and blockade of endothelial NOS with L-NAME had no impact upon the coronary vasodilatory efficacy of testosterone (7,22,26,36,37,39,41).…”

“…L-NAME, an inhibitor of EDRF synthesis did not affect the relaxation by testosterone. Methylene blue, an inhibitor of EDRF induced increase of cGMP, also had no effect on relaxation induced by testosterone (7,22,24,26).…”

Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men

“…30 In addition, it has been shown that testosterone relaxes porcine coronary arteries by opening the largeconductance, calcium-activated potassium channel, 31 and that it attenuates expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVEC), thus inhibiting the adhesion of monocytes to endothelial cells. 32 This phenomenon may help explain the mechanism by which testosterone may have beneficial effects on the cardiovascular system; however, this effect is mediated by endothelial cell aromatase, converting testosterone to estradiol. 32 IMT-CCA has been shown to be associated with the prevalence of cardiovascular disease 33 and atherosclerotic involvement of other arterial beds, including the coronary arteries, 11,12 and to represent a strong predictor of both myocardial infarction and stroke, 13 even in subjects with no history of cardiovascular disease.…”

“…32 This phenomenon may help explain the mechanism by which testosterone may have beneficial effects on the cardiovascular system; however, this effect is mediated by endothelial cell aromatase, converting testosterone to estradiol. 32 IMT-CCA has been shown to be associated with the prevalence of cardiovascular disease 33 and atherosclerotic involvement of other arterial beds, including the coronary arteries, 11,12 and to represent a strong predictor of both myocardial infarction and stroke, 13 even in subjects with no history of cardiovascular disease. 9 Therefore, the results from this study based on IMT-CCA measurements in overweight and obese men may be potentially extrapolated to suggest that hypotesteronemia enhances the susceptibility to atherosclerosis in multiple arterial districts and increases the risk for CHD.…”

Late - Onset Hypogonadism - New Point of View

“…In animal models of isolated coronary, femoral and pulmonary arteries testosterone showed a dose-dependent vasodilatory effect (Channer & Jones, 2003). It is caused by a direct effect on the vascular smooth muscle, by either an effect on potassium or calcium channels (Deenadayalu, V.P., et al 2001, English, K.M., 2002. In man, testosterone has been shown to cause dose-dependent vasodilation both in vitro and in vivo.…”