Possible role of Ca2+ channels in the vasodilating effect of 5beta-dihydrotestosterone in rat aorta.
It has previously been shown that the androgen, 5beta-dihydrotestosterone (17beta-hydroxy-5beta-androstan-3-one, 5beta-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 5beta-dihydrotestosterone, with particular emphasis on verifying a possible interaction with GABA(A) receptors, beta-adrenoceptors and Ca2+ channels. Rat aortic rings without endothelium were isometrically recorded. 5Beta-dihydrotestosterone produced a concentration-dependent relaxation on the contractions induced by noradrenaline (NA; 0.3 microM) or K+ (KCl; 60 mM), with the latter being more sensitive to 5beta-dihydrotestosterone-induced relaxation than the former; the concentration-response curves showed that 5beta-dihydrotestosterone is significantly more potent than 17beta-estradiol(1,3,5(10)-estratrien-3,17beta-diol) to induce vasodilatation. The vasodilating effect of 5beta-dihydrotestosterone on noradrenaline-induced contraction was resistant to blockade by the GABA(A) receptor antagonists, picrotoxin or bicuculline, and the beta-adrenoceptor antagonist, propranolol, a finding that excludes an interaction of the steroid with GABA(A) receptors and beta-adrenoceptors. Interestingly, the contractions evoked by calcium in depolarized tissues were substantially inhibited by 5beta-dihydrotestosterone, implying that this steroid could be an endogenous calcium channel blocker; consistent with this finding, 5beta-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 5beta-dihydrotestosterone. Nifedipine was more potent than 5beta-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 5beta-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.
Perusquía
M
M
Universidad Nacional Autónoma de México, Instituto de Investigaciones Biomédicas, Mexico City D.F., Mexico. perusqui@servidor.unam.mx
Villalón
C M
CM
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011943:Receptors, Adrenergic, beta; D011963:Receptors, GABA-A; D013196:Dihydrotestosterone; D004958:Estradiol; D009638:Norepinephrine