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 exa mined in human isolated subcutaneous resistance arteries. Isolated art eries were mounted on an isometric myograph and loaded with the Ca2+ i ndicator, fura-2, for simultaneous measurement of force and [Ca2+](i). 2 High potassium solution (KPSS), noradrenaline and azepexole increas ed [Ca2+](i) and contracted subcutaneous arteries in physiological sal ine. When extracellular Ca2+ was removed and the calcium chelator, BAP TA, added to the physiological saline (PSS0), responses to noradrenali ne were transient and reduced, and responses to azepexole were markedl y 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 respo nse to caffeine in physiological saline was inhibited by ryanodine. In PSS0, ryanodine partially inhibited contractile responses to noradren aline and azepexole, and completely abolished the response to caffeine . 4 Noradrenaline and azepexole both significantly increased maximum f orce achieved by cumulative addition of Ca2+ to a Ca2+-free depolarizi ng solution and shifted the calculated relationship between [Ca2+](i) and force to the left, suggesting these agents increase the sensitivit y of the contractile apparatus to [Ca2+](i). 5 (-)-202 791, a dihydrop yridine antagonist of voltage-operated calcium channels partially inhi bited 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), l ipoxygenase and cyclo-oxygenase, had no effect on azepexole-induced co ntraction in the presence of N-omega nitro-L-arginine methyl ester. 6 Azepexole, a selective alpha 2-adrenoceptor agonist, contracts human s ubcutaneous resistance arteries by a mechanism largely dependent on th e influx of extracellular Ca2+ probably through voltage-operated calci um channels. This action involves a pertussis toxin-sensitive G protei n, possibly G(i).