D'Alonzo A J, Zhu J L, Darbenzio R B, Dorso C R, Grover G J
Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Cardiovascular Pharmacology, Princeton, NJ 08543-4000, USA.
J Mol Cell Cardiol. 1998 Feb;30(2):415-23. doi: 10.1006/jmcc.1997.0605.
The contribution of adrenergic stimulation to the proarrhythmic effects of pinacidil (30 microM), an opener of ATP-sensitive potassium channels (K+ATP), was tested in an isolated guinea-pig heart model of global ischemia (10 min) and reperfusion (10 min). None (0%) of the control hearts (n=10) elicited arrhythmias during ischemia or reperfusion. In the pinacidil-treated group, one heart (5%) experienced episodes of ventricular tachycardia (VT)/fibrillation (VF) during normoxia. During ischemia, 63% (12 out of 19) of pinacidil-treated hearts exhibited episodes of VT or VF. Hearts not in VT or VF (n=7) at the time of reperfusion, exhibited 71% VT and 43% VT/VF upon reperfusion. Proarrhythmic effects of pinacidil during ischemia or reperfusion were completely reversed by glyburide (n=9; 10 microM), a K+ATP antagonist, or nadolol (n=9; 3 microM), a beta-adrenergic antagonist. Isoproterenol (n=10; 50 nM), a beta-adrenergic agonist, induced a 20% incidence of ischemic VT and VF, and a 70% incidence of reperfusion VF, while methoxamine (n=10; 10 microM), an alpha-adrenergic agonist, demonstrated little proarrhythmia (20% VT/VF at reperfusion only). Proarrhythmic effects of isoproterenol were reversed by nadolol, but not glyburide. Pinacidil caused a slight potentiation of tachycardia induced by a bolus injection of tyramine (30 micro g), an indirectly acting sympathomimetic, but bolus injections of pinacidil (100 micro g) had no effect on heart rate. Nisoxetine, a catecholamine uptake 1 inhibitor, had no proarrhythmic effects when given alone. Catecholamine levels were reduced in pinacidil-treated hearts relative to vehicle-treated. In conclusion, it is suggested that the proarrhythmic effects of pinacidil following global ischemia and reperfusion in the isolated perfused guinea-pig heart appears to involve stimulation of beta-adrenoceptors. These proarrhythmic effects of pinacidil do not appear to be mediated solely through direct opening of K+ATP, but rather through an indirect enhancement of catecholamine release.
在离体豚鼠全心缺血（10分钟）及再灌注（10分钟）模型中，检测了肾上腺素能刺激对吡那地尔（30微摩尔）促心律失常作用的影响，吡那地尔是一种ATP敏感性钾通道（K+ATP）开放剂。对照组心脏（n = 10）在缺血或再灌注期间均未（0%）诱发心律失常。在吡那地尔治疗组中，1颗心脏（5%）在常氧期间出现室性心动过速（VT）/心室颤动（VF）发作。在缺血期间，63%（19颗中的12颗）接受吡那地尔治疗的心脏出现VT或VF发作。再灌注时未处于VT或VF状态的心脏（n = 7），再灌注时出现VT的比例为71%，出现VT/VF的比例为43%。吡那地尔在缺血或再灌注期间的促心律失常作用可被格列本脲（n = 9；10微摩尔）（一种K+ATP拮抗剂）或纳多洛尔（n = 9；3微摩尔）（一种β肾上腺素能拮抗剂）完全逆转。异丙肾上腺素（n = 10；50纳摩尔）（一种β肾上腺素能激动剂）诱发缺血性VT和VF的发生率为20%，再灌注VF的发生率为70%，而甲氧明（n = 10；10微摩尔）（一种α肾上腺素能激动剂）几乎没有促心律失常作用（仅在再灌注时为20%的VT/VF）。异丙肾上腺素的促心律失常作用可被纳多洛尔逆转，但不能被格列本脲逆转。吡那地尔可使大剂量注射酪胺（30微克）（一种间接作用的拟交感神经药）诱发的心动过速稍有增强，但大剂量注射吡那地尔（100微克）对心率无影响。去甲替林（一种儿茶酚胺摄取1抑制剂）单独给药时无促心律失常作用。与溶剂处理组相比，吡那地尔治疗组心脏中的儿茶酚胺水平降低。总之，提示在离体灌注豚鼠心脏中，吡那地尔在全心缺血及再灌注后的促心律失常作用似乎涉及β肾上腺素能受体的刺激。吡那地尔的这些促心律失常作用似乎并非仅通过直接开放K+ATP介导，而是通过间接增强儿茶酚胺释放介导。
