Chen M J, Lee Y M, Sheu J R, Hu C T, Yen M H
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
J Pharm Pharmacol. 1998 Jan;50(1):83-90. doi: 10.1111/j.2042-7158.1998.tb03309.x.
The pharmacological activity of CL-065 (trans-3-acetamido-2,2-dimethyl-4-hydroxy-3,4-dihydro-2H-1-benzopyran-6- carbonitrite) was investigated in anaesthetized spontaneously hypertensive rats (SHR) and isolated thoracic aorta of Sprague-Dawley rats. The intravenous administration of CL-065 [0.1-2.0 mg kg(-1)] to anaesthetized SHR induced a dose-dependent reduction of mean arterial pressure (MAP) with maximum effect approximately 5 min after injection and which persisted for over 3 h. CL-065 also induced a reflex tachycardia which seemed to parallel the time course of the hypotensive effect. The hypotensive effect of CL-065 was blocked by pretreatment with glibenclamide [5 mg kg(-1), i.v.], a specific ATP-sensitive potassium (KATP) channel blocker. Moreover, CL-065 (0.01-10 microM) resulted in dose-dependent vasodilatory effects on phenylephrine (0.3 microM)-induced vasoconstriction in isolated thoracic aorta. The vasorelaxation elicited by CL-065 was antagonized competitively by pretreatment with glibenclamide (0.1-1.0 microM; pA2 = 6.90+/-0.09; slope = 1.03+/-0.18). Similarly, the other two KATP-channel openers cromakalim (1.0 nM-1.0 microM) and nicorandil (0.1-30 microM) also induced vasorelaxation in thoracic aorta. The EC50 of cromakalim, CL-065 and nicorandil (i.e. the doses having half the maximum effect) were approximately 0.083, 0.17, and 4.5 microM, respectively, for phenylephrine (0.3 microM)-induced vasoconstriction in isolated thoracic aorta. Moreover, increased extracellular potassium levels (20-60 mM) resulted in concentration-dependent attenuation of the vasodilator effect of CL-065. In conclusion, CL-065 induces a depressor effect via activation of KATP channels.
在麻醉的自发性高血压大鼠（SHR）和Sprague-Dawley大鼠的离体胸主动脉中研究了CL-065（反式-3-乙酰氨基-2,2-二甲基-4-羟基-3,4-二氢-2H-1-苯并吡喃-6-碳亚硝酸盐）的药理活性。向麻醉的SHR静脉注射CL-065 [0.1 - 2.0 mg kg⁻¹]可引起平均动脉压（MAP）呈剂量依赖性降低，注射后约5分钟达到最大效应，并持续超过3小时。CL-065还引起反射性心动过速，这似乎与降压作用的时间进程平行。CL-065的降压作用被格列本脲[5 mg kg⁻¹，静脉注射]预处理阻断，格列本脲是一种特异性ATP敏感性钾（KATP）通道阻滞剂。此外，CL-065（0.01 - 10 μM）对苯肾上腺素（0.3 μM）诱导的离体胸主动脉血管收缩产生剂量依赖性血管舒张作用。CL-065引起的血管舒张被格列本脲（0.1 - 1.0 μM；pA2 = 6.90±0.09；斜率 = 1.03±0.18）预处理竞争性拮抗。同样，另外两种KATP通道开放剂克罗卡林（1.0 nM - 1.0 μM）和尼可地尔（0.1 - 30 μM）也在胸主动脉中诱导血管舒张。对于苯肾上腺素（0.3 μM）诱导的离体胸主动脉血管收缩，克罗卡林、CL-065和尼可地尔的EC50（即产生最大效应一半的剂量）分别约为0.083、0.17和4.5 μM。此外，细胞外钾水平升高（20 - 60 mM）导致CL-065血管舒张作用呈浓度依赖性减弱。总之，CL-065通过激活KATP通道诱导降压作用。
