Relaxation of androgens on rat thoracic aorta: Testosterone concentration dependent agonist/antagonist L-type Ca2+ channel activity, and 5β-dihydrotestosterone restricted to L-type Ca2+ channel blockade

Abstract

Androgen vasorelaxing action is a subject of recent interest. We investigated the involvement of L-type voltage-operated Ca2+ channels (L-VOCCs), K+ channels, intracellular Ca2+ concentration ([Ca2+]i), and cAMP in the vasorelaxing effect of testosterone and 5β-dihydrotestosterone (5β-DHT) on rat thoracic aorta. Isolated aortic rings were used to study the vasorelaxing potency of testosterone and 5β-DHT on KCl- and noradrenaline-induced contractions. Patch-clamp was used to analyze androgen effects on Ca2+ inward and K+ outward currents. The fluorescence technique was used to evaluate [Ca2+]i in single myocytes; moreover, simultaneous measurements of [Ca2+]i and vascular contraction were evaluated. 5β-DHT was more potent than testosterone to relax KCl-induced contraction, but they were equipotent to relax noradrenaline contraction. L-type Ca2+ currents were blocked by nifedipine, both androgens, and an estrogen in a concentration-dependent manner, and the order of potency was: testosterone > nifedipine > 5β-DHT > 17β-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 μM concentrations it was observed that: 1) its Ca2+ antagonist property is reverted by increasing the L-type inward Ca2+ currents (Ca2+ agonist property); and 2) the [Ca2+]i and cAMP production was increased. The total K + currents were unaffected by testosterone or 5β-DHT. The data show that 5β-DHT-induced vasorelaxation is due to its selective blockade on L-VOCCs (from nM to μM concentrations), but testosterone-induced vasorelaxation involves concentration-dependent additional mechanisms: acting as an L-VOCCs antagonist at low concentrations, and increasing [Ca2+]i and cAMP production at high concentrations. Copyright © 2008 by The Endocrine Society.