Cicletanine-Induced Decreases in Cytosolic Ca^<2+> Level and Contraction in Vascular Smooth Muscle

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The mechanism by which cicletanine (3-(4-chlorophenyl)-1, 3-dihydro-7-hydroxy-6-methylfuro-[3, 4-c]pyridine) induces vasodilatation was examined in isolated vascular smooth muscle. Cicletanine inhibited the contraction induced by high K+, norepinephrine (NE) and prostaglandin F2α in a concentration-dependent manner in rat aorta. High K+ (15.8 – 72.7 mM) elicited elevation of cytosolic Ca2+ level ([Ca2+]i) and contraction in a concentration-dependent manner. Cicletanine (300 μM) inhibited the high K+-induced 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 contractile 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 by caffeine in Ca2+-free solution. Cicletanine did not inhibit contraction induced by Ca2+ in the permeabilized rabbit mesenteric artery with α-toxin. These results suggest that cicletanine inhibits vascular smooth muscle contraction by multiple mechanisms: 1) inhibition of Ca2+ influx via voltage-dependent Ca2+ channel and 2) inhibition of Ca2+ release mediated by the α-adrenoceptors, but not by caffeine.
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