Cicletanine-induced decreases in cytosolic Ca2+ level and contraction in vascular smooth muscle.
The mechanism by which cicletanine (3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]pyri dine) 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.
Izumi
M
M
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan.
Mitsui-Saito
M
M
Ozaki
H
H
Karaki
H
H
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D006152:Cyclic GMP / Q000032:analysis; D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism; D015237:Dinoprost; D004305:Dose-Response Relationship, Drug; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine; D011189:Potassium Chloride; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D000959:Antihypertensive Agents; D000697:Central Nervous System Stimulants; D011725:Pyridines; D011942:Receptors, Adrenergic, alpha; D002110:Caffeine; D011189:Potassium Chloride; D015237:Dinoprost; C038068:cicletanine; D006152:Cyclic GMP; D002118:Calcium; D009638:Norepinephrine