Possible role of Ca 2+ channels in the vasodilating effect of 5β-dihydrotestosterone in rat aorta

Abstract

It has previously been shown that the androgen, 5β-dihydrotestosterone (17β-hydroxy-5β-androstan-3-one, 5β-DHT), is able to produce an endothelium-independent vasodilating effect in rat aorta. The present study analyzed the mechanisms underlying the above vasodilator effect of 5β-dihydrotestosterone, with particular emphasis on verifying a possible interaction with GABA A receptors, β-adrenoceptors and Ca 2+ channels. Rat aortic rings without endothelium were isometrically recorded. 5β-Dihydrotestosterone produced a concentration-dependent relaxation on the contractions induced by noradrenaline (NA; 0.3 μM) or K + (KCl; 60 mM), with the latter being more sensitive to 5β-dihydrotestosterone-induced relaxation than the former; the concentration–response curves showed that 5β-dihydrotestosterone is significantly more potent than 17β-estradiol (1,3,5(10)-estratrien-3,17β-diol) to induce vasodilatation. The vasodilating effect of 5β-dihydrotestosterone on noradrenaline-induced contraction was resistant to blockade by the GABA A receptor antagonists, picrotoxin or bicuculline, and the β-adrenoceptor antagonist, propranolol, a finding that excludes an interaction of the steroid with GABA A receptors and β-adrenoceptors. Interestingly, the contractions evoked by calcium in depolarized tissues were substantially inhibited by 5β-dihydrotestosterone, implying that this steroid could be an endogenous calcium channel blocker; consistent with this finding, 5β-dihydrotestosterone was able to relax tissues precontracted with the calcium channel opener, Bay K 8644. Moreover, although the rings precontracted with noradrenaline and potassium were almost equipotently relaxed by 5β-dihydrotestosterone. Nifedipine was more potent than 5β-dihydrotestosterone to block the potassium-induced contraction, but the steroid was more effective than nifedipine to prevent noradrenaline-induced contraction. The above results suggest that 5β-dihydrotestosterone causes relaxation of rat aorta by acting directly on the membrane of smooth muscle cells; this non-genomic action may be explained in terms of a blockade of voltage- and receptor-dependent calcium channels, a mechanism that restricts the availability of extracellular calcium in the contractile machinery.