Verapamil: a selective antagonist of constrictor substances in dog coronary artery: implications for variant angina

1. Canine circumflex coronary artery ring segments were contracted in vitro by ergometrine, serotonin, phenylephrine, noradrenaline (with propranolol) and a thromboxane A2 analogue, U46619. 2. Ergometrine was classified as a serotonin agonist since concentration-response curves were competitively inhibited by methysergide but not by alpha-adrenoceptor antagonists. 3. Glyceryl trinitrate (IC50 18.6 nmol/l) relaxed the coronary rings precontracted with serotonin, phenylephrine or U46619. In contrast (+/-)-verapamil (0.1-10 mumol/l) was more effective against serotonin than phenylephrine or noradrenaline and was almost inactive against U46619. 4. In a blood perfused left anterior descending coronary artery preparation external diameter was measured by sonomicrometry. Serotonin, U46619 and ergometrine infusions (i.a.) decreased diameter by up to 18% without causing spasm (zero lumen diameter). Lowering the perfusion pressure from 90 to 60 mmHg increased the fall in diameter during serotonin infusions. 5. The negative inotropic potency of verapamil against noradrenaline induced beta-adrenergic stimulation in guinea-pig left atria was compared with the vasodilator potency of verapamil in noradrenaline constricted dog coronary artery rings. Verapamil was eighteen times more potent in cardiac muscle than in coronary smooth muscle. 6. This apparent tissue selectivity of verapamil was confirmed in anaesthetized dogs where plasma concentrations of verapamil 50-150 ng/ml (in the therapeutic range) lowered blood pressure and heart rate and increased P-R interval without greatly reducing the constrictor response to serotonin in the coronary artery. 7. These studies suggest that inhibition of constrictor responses in large coronary vessels may not be an important site of action of verapamil in patients with variant angina.