The long-lasting anti-anginal effects of CP-0605 in a rat model of arginine vasopressin-induced myocardial ischaemia

Abstract

Abstract 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 (≅ 50 nwi), 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 μg kg−1 and diltiazem at 500 μg kg−1 showed similar haemodynamic changes, whereas CP-060S, at 300 μg kg−1, significantly suppressed AVP-induced ST-segment depression and diltiazem, at 500 μg 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.