Differential inhibitory effects of the ionophore RO2-2985 (X537A) on contractile responses to potassium and histamine in coronary artery smooth muscle.

The effects of the ionophore RO2-2985 (X537A) on KCl- and histamine-induced contractions in porcine coronary vascular smooth muscle were studied in vitro. Cumulative dose-response curves were constructed for KCl and histamine in the presence and absence of RO2-2985. The dose-response curve to KCl in the presence of RO2-2985 was shifted to the right with no change in the maximal response attained. Lineweaver-Burk and Hill plots indicated that responses to KCl involved a positive cooperative interaction between excitation and some step or steps in the contractile event and that RO2-2985 increased this cooperativity. The dose-response curve to histamine in the presence of the ionophore was significantly shifted to the right with a 40 to 50% depression in the maximal response. Propranolol inhibited norepinephrine-induced relaxation of KCl-contracted coronary strips but did not affect RO2-2985-induced relaxation. These results suggest that RO2-2985 competitively inhibits KCl-induced contractions but inhibition of histamine-induced contractions are of a mixed mechanism. Also, RO2-2985 does not appear to induce relaxation of coronary artery smooth muscle by liberating enodgenous catecholamines. Preliminary evidence supports involvement of prostaglandins in the mechanism of ionophore-induced coronary relaxation.