Vasodilator Actions of Flunarizine in Isolated Dog Cerebral and Extracerebral Arteries

Abstract

Flunarizine relaxed isolated canine arteries precontracted with prostaglandin (PG) F_2α, epithio-methano-thromboxane A₂ and K⁺; the relaxation was in the order of cerebral>renal>mesenteric=coronary arteries, when contracted with PGF_2α or the thromboxane A₂ analogue. Flunarizine-induced relaxation was unaffected by treatment with atropine, propranolol, cimetidine, chlorpheniramine, aminophylline and indomethacin, and by removal of endothelium. Under normoxia, flunarizine attenuated contractions elicited by Ca²⁺ in the K⁺-stimulated cerebral and mesenteric arteries that had been previously exposed to Ca²⁺-free media to a greater extent than that in PGF_2α-stimulated preparations. The Ca²⁺-induced contraction in cerebral arteries was more sensitive to flunarizine than that in mesenteric arteries. Contractions caused by PGF_2α in Ca²⁺-free media were not influenced by flunarizine. In cerebral and mesenteric arteries that had been previously exposed to Ca²⁺-free media and severe hypoxia and then stimulated by PGF_2α and Ca²⁺, reoxygenation produced a persistent contraction. Flunarizine suppressed the reoxygenation induced-contraction. It is concluded that flunarizine dilates cerebral arteries predominantly over the other arteries; the vasodilatation appears to derive from an interference with the transmembrane Ca²⁺ influx that occurs through a voltage-dependent process and, to a lesser extent, receptor-operated channels, but not with the Ca²⁺ release from stored sites. Contraction induced by reoxygenation is expected to be due mainly to the transmembrane influx of Ca²⁺, which is also suppressed by flunarizine.