Masanori Izumi, Minori Mitsui-Saito, Hiroshi Ozaki and Hideaki Karaki
Department of Veterinary Pharmacology, Graduate School of Agriculture
and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113, Japan
Abstract: 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 F2alpha 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 microM) 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 alpha-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 alpha-adrenoceptors,
but not by caffeine.
Keywords: Cicletanine, Smooth muscle (vascular), Ca2+ sensitivity, cGMP,
Aorta (rat)