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

• Published in: Endocrinology (Philadelphia) Vol. 149; no. 5; p. 2517
• Main Authors: Montaño, Luis M, Calixto, Eduardo, Figueroa, Alejandra, Flores-Soto, Edgar, Carbajal, Verónica, Perusquía, Mercedes
• Format: Journal Article
• Language: English
• Published: United States 01.05.2008
• Subjects: Androgens - pharmacology; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiology; Calcium - metabolism; Calcium Channel Agonists - pharmacology; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - metabolism; Cells, Cultured; Dihydrotestosterone - pharmacology; Dose-Response Relationship, Drug; Male; Membrane Potentials - drug effects; Muscle Cells; Osmolar Concentration; Potassium - metabolism; Rats; Rats, Wistar; Substrate Specificity; Testosterone - pharmacology; Vasodilation - drug effects
• ISSN: 0013-7227
• DOI: 10.1210/en.2007-1288

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.