Relaxation of androgens on rat thoracic aorta: testosterone concentration dependent agonist/antagonist L-type Ca2+ channel activity, and 5beta-dihydrotestosterone restricted to L-type Ca2+ channel blockade.
Androgen vasorelaxing action is a subject of recent interest. We investigated the involvement of l-type voltage-operated Ca(2+) channels (L-VOCCs), K(+) channels, intracellular Ca(2+) concentration ([Ca(2+)]i), and cAMP in the vasorelaxing effect of testosterone and 5beta-dihydrotestosterone (5beta-DHT) on rat thoracic aorta. Isolated aortic rings were used to study the vasorelaxing potency of testosterone and 5beta-DHT on KCl- and noradrenaline-induced contractions. Patch-clamp was used to analyze androgen effects on Ca(2+) inward and K(+) outward currents. The fluorescence technique was used to evaluate [Ca(2+)]i in single myocytes; moreover, simultaneous measurements of [Ca(2+)]i and vascular contraction were evaluated. 5beta-DHT was more potent than testosterone to relax KCl-induced contraction, but they were equipotent to relax noradrenaline contraction. l-type Ca(2+) currents were blocked by nifedipine, both androgens, and an estrogen in a concentration-dependent manner, and the order of potency was: testosterone > nifedipine > 5beta-DHT > 17beta-estradiol. We observed that testosterone has different mechanism of action by the concentration range used: at nm concentrations it was a powerful L-VOCCs antagonist, whereas at mum concentrations it was observed that: 1) its Ca(2+) antagonist property is reverted by increasing the l-type inward Ca(2+) currents (Ca(2+) agonist property); and 2) the [Ca(2+)]i and cAMP production was increased. The total K(+) currents were unaffected by testosterone or 5beta-DHT. The data show that 5beta-DHT-induced vasorelaxation is due to its selective blockade on L-VOCCs (from nm to microm concentrations), but testosterone-induced vasorelaxation involves concentration-dependent additional mechanisms: acting as an L-VOCCs antagonist at low concentrations, and increasing [Ca(2+)]i and cAMP production at high concentrations.
Montaño
Luis M
LM
Instituto de Investigaciones Biomédicas, Departamento de Biología Celular y Fisiología, and Facultad de Medicina, Departamento de Farmacología, México D.F. 04510.
Calixto
Eduardo
E
Figueroa
Alejandra
A
Flores-Soto
Edgar
E
Carbajal
Verónica
V
Perusquía
Mercedes
M
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D032342:Muscle Cells; D009994:Osmolar Concentration; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity; D013739:Testosterone / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D000728:Androgens; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D013196:Dihydrotestosterone; D013739:Testosterone; D011188:Potassium; D002118:Calcium