Flunarizine inhibits endothelium-dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle

Abstract

1. Hypoxia augments contractile responses to several vasoactive agents in canine isolated coronary arteries with intact endothelium. Calcium antagonists inhibit the further increases in tension caused by hypoxia. The present experiments were designed to determine whether the calcium-antagonist flunarizine would inhibit hypoxic contractions in isolated blood vessels through an action on the endothelium or on the vascular smooth muscle. 2. Rings of canine coronary arteries, with or without endothelium, were suspended at optimal length for isometric tension recording in organ chambers filled with modified Krebs-Ringer bicarbonate solution. 3. Hypoxia (95% N2 and 5% CO2) augmented contractile responses to prostaglandin F(2α) (2 x 10-6 M); removal of the endothelium abolished this hypoxic facilitation. 4. Flunarizine (5 x 10-5-5 x 10-7 M) exerted a long-lasting inhibition of the hypoxic facilitation in a concentration-dependent manner. Flunarizine did not inhibit the response to prostaglandin F(2α). 5. To differentiate between the response of smooth muscle and the endothelium, strips of coronary arteries without endothelium were layered with strips with or without endothelium. Hypoxia augmented contractions only in layered preparations with endothelium. Flunarizine prevented the hypoxic contractions in layered preparations in which only the smooth muscle was treated with flunarizine. In contrast, when only the endothelium was treated, no or minimal inhibition of the hypoxic contraction occurred with flunarizine (10-5 and 5 x 10-5 M, respectively). 6. These experiments indicate that the calcium antagonist flunarizine inhibits endothelium-dependent hypoxic facilitation in canine coronary arteries primarily through its action on vascular smooth muscle.