Inhibition of endothelium-dependent hyperpolarization by endothelial prostanoids in guinea-pig coronary artery

1 In smooth muscle of the circumflex coronary artery of guinea-pig, acetylcholine (ACh, 10(-6) M) produced an endothelium-dependent hyperpolarization consisting of two components. An initial component that occurs in the presence of ACh and a slow component that developed after ACh had been withdrawn. Each component of the hyperpolarization was accompanied by an increase in membrane conductance. 2 Indomethacin (5 x 10(-6) M) or diclofenac (10(-6) M), both inhibitors of cyclooxygenase, abolished only the slow hyperpolarization. The initial hyperpolarization was not inhibited by diclofenac nor by nitroarginine, an inhibitor of nitric oxide synthase. 3 Both components of the ACh-induced hyperpolarization were abolished in the presence of atropine (10(-6) M) or high-g solution ([K+](0)=29.4 mM). 4 The interval between ACh-stimulation required to generate an initial hyperpolarization of reproducible amplitude was 20 min or greater, but it was reduced to less than 5 min after inhibiting cyclooxygenase activity. Conditioning stimulation of the artery with substance P (10(-7) M) also caused a long duration (about 20 min) inhibition of the ACh-response. 5 The amplitude of the hyperpolarization generated by Y-2.6763, a K+-channel opener, was reproducible within 10 min after withdrawal of ACh. 6 Exogenously applied prostacyclin (PGI(2)) hyperpolarized the membrane and reduced membrane resistance in concentrations over 2.8 x 10(-9) M. 7 At concentrations below threshold for hyperpolarization and when no alteration of membrane resistance occurred, PGI(2) inhibited the initial component of the ACh-induced hyperpolarization. 8 It is concluded that endothelial prostanoids, possibly PGI(2), have an inhibitory action on the release of endothelium-derived hyperpolarizing factor.