Mechanisms of vasoinhibitory effect of cardioprotective agent, CP-060S, in rat aorta.
Vasoinhibitory effects of (-)-(S)-2-[3,5-bis(1, 1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[N-methyl-N-[2-(3, 4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin- 4-one hydrogen fumarate (CP-060S), a synthesized cardioprotective agent, were examined. In the rat aortic rings, the contractile responses to cumulative application of angiotensin II, [Arg(8)]-vasopressin (vasopressin), or prostaglandin F(2alpha) were inhibited by CP-060S in a concentration-dependent manner. The Ca(2+)-induced contractions in the presence of vasopressin or prostaglandin F(2alpha) were also inhibited by CP-060S in a concentration-dependent manner. The inhibitory effect of 10(-5) M CP-060S on phenylephrine-induced contraction was as potent as that of 10(-6) M nifedipine, and the combined addition of 10(-6) M nifedipine and 10(-5) M CP-060S showed the effect similar to that of 10(-5) M CP-060S alone. In rat aorta loaded with a Ca(2+) indicator, fura-PE3, 10(-5) M CP-060S completely inhibited the high K(+)-induced increase in cytosolic Ca(2+) level ([Ca(2+)](i)) and contraction. In contrast, 10(-5) M CP-060S only partially inhibited the increase in [Ca(2+)](i) and contraction due to phenylephrine or prostaglandin F(2alpha). In the presence of 10(-6) M nifedipine, 10(-5) M CP-060S did not inhibit the increase in [Ca(2+)](i) and contraction induced by prostaglandin F(2alpha). In a Ca(2+)-free medium, the phasic increases in contraction and [Ca(2+)](i) induced by phenylephrine were not affected by 10(-5) M CP-060S. These results suggest that the vasoinhibitory effect of CP-060S in rat aortic rings is due mainly to the inhibition of L-type voltage-dependent Ca(2+)-channels.
Sato
K
K
Radio Isotope Center, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-Ku, 113-8657, Tokyo, Japan.
Satake
N
N
Shibata
S
S
Adachi
Y
Y
Karaki
H
H
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D015237:Dinoprost / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; C104781:CP 060S; D002121:Calcium Channel Blockers; D013844:Thiazoles; D053778:Thiazolidines; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D001127:Arginine Vasopressin; D010656:Phenylephrine; D015237:Dinoprost; D009543:Nifedipine; D002118:Calcium