CICLETANINE-INDUCED DECREASES IN CYTOSOLIC CA2-MUSCLE( LEVEL AND CONTRACTION IN VASCULAR SMOOTH)

The mechanism by which cicletanine ,3-dihydro-7-hydroxy-6-methylfuro-[ 3,4-c]pyridine) induces vasodilatation was examined in isolated vascul ar smooth muscle. Cicletanine inhibited the contraction induced by hig h K+, norepinephrine (NE) and prostaglandin F-2a in a concentration-de pendent manner in rat aorta. High K+ (15.8-72.7 mM) elicited elevation of cytosolic Ca2+ level ([Ca2+](i)) and contraction in a concentratio n-dependent manner. Cicletanine (300 (IM) inhibited the high K+-induce d contractions without changing the [Ca2+](i)/tension relationship. NE (3-300 nM) elicited greater contractions than high K+ at a given [Ca2 +](i), suggesting that NE increased Ca2+ sensitivity of the contractil e elements. Cicletanine inhibited the NE-induced contractions without changing the slope of the [Ca2+](i)/tension relationship. Cicletanine inhibited the transient increases in both [Ca2+](i) and muscle tension elicited by NE but not the transient increase in [Ca2+](i) elicited b y caffeine in Ca2+-free solution. Cicletanine did not inhibit contract ion induced by Ca2+ in the permeabilized rabbit mesenteric artery with alpha-toxin. These results suggest that cicletanine inhibits vascular smooth muscle contraction by multiple mechanisms: 1) inhibition of Ca 2+ influx via voltage-dependent Ca2+ channel and 2) inhibition of Ca2 release mediated by the alpha-adrenoceptors, but not by caffeine.