The long-lasting anti-anginal effects of CP-060S in a rat model of arginine vasopressin-induced myocardial ischaemia.
The anti-anginal effect of CP-060S, a new cardioprotective agent that prevents myocardial Na+-, Ca2+-overload and has Ca2+-channel blocking activity, was evaluated in a rat model of arginine8-vasopressin (AVP)-induced cardiac ischaemia. Infusion of AVP (0.2 IU kg(-1)) depressed the electrocardiogram (ECG) ST segment, an index of myocardial ischaemia. Vehicle, CP-060S and diltiazem were given orally 1, 2, 4, 8, 12 and 24 h before the administration of AVP. CP-060S, at 3 mg kg(-1) and 10 mg kg(-1), suppressed AVP-induced ST-segment depression for 2 h and 12 h, respectively. In contrast, diltiazem, at 10 and 30 mg kg(-1), suppressed AVP-induced ST-segment depression for only 1 h. The persistent suppression of the AVP-induced ST-segment depression by CP-060S correlated with the time course of changes in its plasma concentration. The minimum effective concentration of CP-060S was estimated to be 30 ng mL(-1) (approximately 50 nM), consistent with its vasorelaxant potency in rat isolated aortic strips (concentration producing 50% relaxation of KCl contraction, IC50 = 32.6+/-8.3 nM). Intravenously administered CP-060S, at 300 microg kg(-1) and diltiazem at 500 microg kg(-1) showed similar haemodynamic changes, whereas CP-060S, at 300 microg kg(-1), significantly suppressed AVP-induced ST-segment depression and diltiazem, at 500 microg kg(-1), had no effect on AVP-induced ST-segment depression. In summary, orally administered CP-060S exerted a long-lasting anti-anginal effect proportionate to the time course of changes in its plasma concentration in a rat model of AVP-induced ischaemia.
Adachi
Yuichiro
Y
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd, Gotemba-shi, Shizuoka, Japan.
Suzuki
Yoshiyuki
Y
Hatanaka
Takahiro
T
Fukazawa
Masanori
M
Tamura
Kazuhiko
K
D000818:Animals; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D004110:Diltiazem / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000627:therapeutic use*; D053778:Thiazolidines; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000633:toxicity
C104781:CP 060S; D002121:Calcium Channel Blockers; D013844:Thiazoles; D053778:Thiazolidines; D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin; D004110:Diltiazem