Mechanisms of flunarizine-induced vasodilation in the rabbit mesenteric artery.
The vasodilating effects of flunarizine on smooth muscle strips of rabbit mesenteric artery have been investigated and compared with those of nifedipine. Flunarizine (30-300 nM) dose-dependently inhibited Ca2+-induced contractions in Ca2+-free solution containing 100 mM K+. Double reciprocal analysis showed that this inhibition was either competitive at low concentrations (30-100 nM; nifedipine-like) or noncompetitive at high concentrations (0.3-1 microM). The latter seemed to be partly related to an inhibition of contractile proteins as estimated from Ca2+-induced contractions in saponin-treated chemically skinned muscle strips. In contrast to the actions of nifedipine, flunarizine inhibited norepinephrine (NE)-induced contractions more than those induced by high K+, and at 0.3 microM, this agent totally blocked NE-induced contraction. Flunarizine also inhibited NE-induced contraction in Ca2+-free solution containing 2 mM EGTA. In Ca2+-free solution, NE rapidly hydrolyzed phosphatidylinositol 4,5-bisphosphate (PI-P2) and produced phosphatidic acid (PA). Flunarizine (30 and 300 nM), but not nifedipine (100 nM), inhibited NE-induced hydrolysis of PI-P2 and production of PA. However, flunarizine (100 nM) did not modify the contraction induced by 10 microM inositol 1,4,5-trisphosphate in chemically skinned muscle strips. It is concluded that flunarizine inhibits both voltage-dependent (nifedipine-like) and receptor-operated Ca2+ influx induced by NE and also inhibits NE-induced Ca2+ release from intracellular stores due to inhibition of the hydrolysis of PI-P2.
D000818:Animals; D001696:Biomechanical Phenomena; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D005444:Flunarizine / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D014664:Vasodilation
D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D002110:Caffeine; D009543:Nifedipine; D005444:Flunarizine; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine