Adachi Yuichiro, Suzuki Yoshiyuki, Hatanaka Takahiro, Fukazawa Masanori, Tamura Kazuhiko
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd, Gotemba-shi, Shizuoka, Japan.
J Pharm Pharmacol. 2002 Mar;54(3):413-8. doi: 10.1211/0022357021778484.
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.
CP-060S是一种新型心脏保护剂，可防止心肌钠、钙超载并具有钙通道阻滞活性，在精氨酸8-血管加压素（AVP）诱导的心脏缺血大鼠模型中评估了其抗心绞痛作用。输注AVP（0.2 IU kg⁻¹）会压低心电图（ECG）ST段，这是心肌缺血的一个指标。在给予AVP前1、2、4、8、12和24小时口服赋形剂、CP-060S和地尔硫䓬。CP-060S剂量为3 mg kg⁻¹和10 mg kg⁻¹时，分别抑制AVP诱导的ST段压低2小时和12小时。相比之下，地尔硫䓬剂量为10和30 mg kg⁻¹时，仅抑制AVP诱导的ST段压低1小时。CP-060S对AVP诱导的ST段压低的持续抑制作用与其血浆浓度变化的时间过程相关。CP-060S的最低有效浓度估计为30 ng mL⁻¹（约50 nM），与其在大鼠离体主动脉条中的血管舒张效力一致（产生KCl收缩50%舒张的浓度，IC50 = 32.6±8.3 nM）。静脉注射CP-060S剂量为300 μg kg⁻¹和地尔硫䓬剂量为500 μg kg⁻¹时显示出相似的血流动力学变化，而CP-060S剂量为300 μg kg⁻¹时显著抑制AVP诱导的ST段压低，地尔硫䓬剂量为500 μg kg⁻¹时对AVP诱导的ST段压低无影响。总之，在AVP诱导的缺血大鼠模型中，口服CP-060S产生了与血浆浓度变化时间过程成比例的持久抗心绞痛作用。
