THE MECHANISM OF ACTION OF ALPHA(2)-ADRENOCEPTORS IN HUMAN ISOLATED SUBCUTANEOUS RESISTANCE ARTERIES

1 The effect of noradrenaline and the selective alpha(2)-adrenoceptor agonist, azepexole, on tone and intracellular Ca2+ ([Ca2+](i)) was examined in human isolated subcutaneous resistance arteries. Isolated arteries were mounted on an isometric myograph and loaded with the Ca2+ indicator, fura-2, for simultaneous measurement of force and [Ca2+](i). 2 High potassium solution (KPSS), noradrenaline and azepexole increased [Ca2+](i) and contracted subcutaneous arteries in physiological saline. When extracellular Ca2+ was removed and the calcium chelator, BAPTA, added to the physiological saline (PSS0), responses to noradrenaline were transient and reduced, and responses to azepexole were markedly inhibited. 3 Ryanodine, an agent which interferes with Ca2+ release from intracellular stores, had little effect on contractile responses to KPSS, noradrenaline or azepexole in physiological saline. The response to caffeine in physiological saline was inhibited by ryanodine. In PSS0, ryanodine partially inhibited contractile responses to noradrenaline and azepexole, and completely abolished the response to caffeine. 4 Noradrenaline and azepexole both significantly increased maximum force achieved by cumulative addition of Ca2+ to a Ca2+-free depolarizing solution and shifted the calculated relationship between [Ca2+](i) and force to the left, suggesting these agents increase the sensitivity of the contractile apparatus to [Ca2+](i). 5 (-)-202 791, a dihydropyridine antagonist of voltage-operated calcium channels partially inhibited both the contractile response and the rise in [Ca2+](i) induced by azepexole. Pre-treatment of arteries with pertussis toxin inhibited responses to azepexole, but had no significant effect on tone induced by KPSS or noradrenaline. ETYA, an inhibitor of phospholipase A(2), lipoxygenase and cyclo-oxygenase, had no effect on azepexole-induced contraction in the presence of N-omega nitro-L-arginine methyl ester. 6 Azepexole, a selective alpha 2-adrenoceptor agonist, contracts human subcutaneous resistance arteries by a mechanism largely dependent on the influx of extracellular Ca2+ probably through voltage-operated calcium channels. This action involves a pertussis toxin-sensitive G protein, possibly G(i).