title: Mechanisms of flunarizine-induced vasodilation in the rabbit mesenteric artery.
abstract: 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.
mesh_terms: 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
chemical_list: D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D002110:Caffeine; D009543:Nifedipine; D005444:Flunarizine; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine