Pii: s0014-2999(00)00358-7

Mechanisms of vasoinhibitory effect of cardioprotective agent, Koichi Sato a, Nobuhiro Satake b, Shoji Shibata b,), Yuichiro Adachi c, Hideaki Karaki d a Radio Isotope Center, Graduate School of Agriculture and Life Sciences, The UniÕersity of Tokyo, Bunkyo-Ku, Tokyo 113-8657, Japan b Department of Pharmacology, UniÕersity of Hawaii, School of Medicine Honolulu, Honolulu, HI 96822, USA c Chugai Pharmaceutical Co., Fuji Gotemba Research Laboratories, Shizuoka 412, Japan d Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The UniÕersity of Tokyo, Received 13 January 2000; received in revised form 25 April 2000; accepted 9 May 2000 Abstract
1,1-dimethylethyl -4-hydroxyphenyl -3- 3- N-methyl-N- 2 Ž ethyl amino propyl -1,3-thiazolidin-4-one hydrogen fumarate Ž CP-060S , a synthesized cardioprotective agent, were examined. In the rat aortic rings, the contractile responses to cumulative application of angiotensin II, Arg -vasopressin Ž were inhibited by CP-060S in a concentration-dependent manner. The Ca2q-induced contractions in the presence of vasopressin orprostaglandin F were also inhibited by CP-060S in a concentration-dependent manner. The inhibitory effect of 10y5 M CP-060S on phenylephrine-induced contraction was as potent as that of 10y6 M nifedipine, and the combined addition of 10y6 M nifedipine and10y5 M CP-060S showed the effect similar to that of 10y5 M CP-060S alone. In rat aorta loaded with a Ca2q indicator, fura-PE3, 10y5 M CP-060S completely inhibited the high K -induced increase in cytosolic Ca CP-060S only partially inhibited the increase in Ca and contraction due to phenylephrine or prostaglandin F M CP-060S did not inhibit the increase in Ca and contraction induced by prostaglandin F medium, the phasic increases in contraction and Ca induced by phenylephrine were not affected by 10 suggest that the vasoinhibitory effect of CP-060S in rat aortic rings is due mainly to the inhibition of L-type voltage-dependentCa2q-channels. q 2000 Elsevier Science B.V. All rights reserved.
Keywords: CP-060S; Aorta, rat; Ca2q channel, L-type voltage-dependent; Ca2q, Cytosolic 1. Introduction
phenoxy ethyl amino propyl -1,3-thiazolidin-4-one hydro-gen fumarate Ž CP-060S , a recently synthesized cardiopro- Antagonists of the L-type voltage-dependent Ca2q tective agent, not only caused vasorelaxation of rat isolated channel have been demonstrated in clinical studies to have aorta by inhibition of L-type Ca2q channels, but also beneficial effects in the treatment of hypertension, angina prevented the veratridine-induced Ca2q overload in car- pectoris and arrhythmia. A new generation of Ca2q chan- diomyocytes by the mechanism not related to Ca2q entry nel antagonists appears to be useful, not only in the blockade ŽTamura et al., 1996; Adachi et al., treatment of cardiovascular disease, but also in disease of blockade of Naq channels or inhibition of NaqrCa2q the central nervous system, including focal and global exchange was suggested to be a possible mechanism by cerebral ischemia and age-related cognition deficits and inhibit ischemia- and reperfusion-induced arrhythmia in hydroxyphenyl -3- 3- N-methyl-N- 2 Ž dial infarct size in anesthetized dogs ŽSuzuki et al., In guinea pig papillary muscles and cardiomyocytes, CP-060S was reported to inhibit not only Ca2q currents by ) Corresponding author. Tel.: q1-808-956-0997; fax: q1-808-956- interacting with three principal binding sites on the L-type E-mail address: tonaga@hawaii.edu ŽS.
Ca2q channel, but also non-inactivating Naq currents 0014-2999r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 0 1 4 - 2 9 9 9 Ž 0 0. 0 0 3 5 8 - 7 K. Sato et al.r European Journal of Pharmacology 400 ( ŽSuzuki et al., 1998b; Fukuzawa et al., 1997; Tanabe et al., tension of 20 mN was applied to each muscle strip. The 1997. In guinea pigs mesenteric arteries, CP-060S exhib- isometric tension was recorded through a force-displace- ited the profile of the L-type Ca2q channel antagonists, similar to that of diltiazem and gallopamil, whereas higher concentrations of CP-060S inhibited the delayed Kq chan-nel currents ŽOhya et al., 2.2. Cytosolic Ca2 q leÕel suggest that CP-060S has multiple sites of action in bothsmooth and cardiac muscles.
The thoracic aorta was isolated as described above and To know the precise mechanism of vasodilator effects cut into helical strips Ž2-3 mm wide and 8-10 mm of CP-060S, in the present experiments, we examined the effect of this compound on muscle tension and cytosolic Ca2q indicator, fura-PE3, simultaneously with muscle ten- 1988. Muscle rings were loaded with 5 = 10

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