Sanguinetti M C, Scott A L, Zingaro G J, Siegl P K
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Proc Natl Acad Sci U S A. 1988 Nov;85(21):8360-4. doi: 10.1073/pnas.85.21.8360.
The mechanism by which the antihypertensive agent BRL 34915 (cromakalim) affects action potential duration (APD) and effective refractory period (ERP) in isolated cardiac muscle was investigated. BRL 34915 (greater than or equal to 3 microM) shortened ERP of ferret (Mustela putorius furo) and guinea pig (Cavia porcellus) papillary muscles in a concentration-dependent fashion. The reduction in ERP resulted from a decrease in APD. ERP and APD of papillary muscles were also reduced during hypoxia produced by bubbling the physiological bathing solution with N2 instead of O2. Reduction of APD during hypoxia has previously been attributed to activation of ATP-sensitive K+ channels in heart. Glyburide, an inhibitor of ATP-sensitive K+ channels, prevented or reversed the shortening of ERP and APD produced by hypoxia and BRL 34915, respectively. These results suggest that BRL 34915 acts by opening ATP-sensitive K+ channels in heart. The actions of BRL 34915 were temperature-dependent, decreasing ERP 64% at 37 degrees C, but having no effect at 22 degrees C. The effect of BRL 34915 on K+ currents was tested directly in voltage-clamped guinea pig ventricular myocytes. As observed with the papillary muscles, BRL 34915 was without effect at 22 degrees C. At 36 degrees C, BRL 34915 (after a delay) increased outward currents positive to, and less so at potentials negative to, the K+ current reversal potential. The normal inwardly rectifying current-voltage relationship for peak K+ currents during 200-msec pulses was changed to one that was nearly ohmic. The current activated by BRL 34915 was blocked by glyburide. The data support the hypothesis that BRL 34915, like hypoxia, activates ATP-sensitive K+ channels in the heart. Based upon the profound temperature sensitivity of BRL 34915 action, this activation may be indirect, perhaps by means of modulation of an enzymatic activity that regulates gating of these channels. BRL 34915 and glyburide will be valuable tools for studying the role of ATP-sensitive K+ channels in normal and abnormal cardiac function.
研究了抗高血压药物BRL 34915（克罗卡林）影响离体心肌动作电位时程（APD）和有效不应期（ERP）的机制。BRL 34915（大于或等于3 microM）以浓度依赖性方式缩短雪貂（鼬属）和豚鼠乳头肌的ERP。ERP的缩短是由于APD的减少。在用氮气而非氧气鼓泡生理浴液产生的缺氧过程中，乳头肌的ERP和APD也降低。缺氧期间APD的降低先前被归因于心脏中ATP敏感性钾通道的激活。格列本脲是一种ATP敏感性钾通道抑制剂，分别阻止或逆转了缺氧和BRL 34915引起的ERP和APD的缩短。这些结果表明BRL 34915通过打开心脏中的ATP敏感性钾通道起作用。BRL 34915的作用是温度依赖性的，在37℃时使ERP降低64%，但在22℃时无作用。在电压钳制的豚鼠心室肌细胞中直接测试了BRL 34915对钾电流的影响。如在乳头肌中观察到的那样，BRL 34915在22℃时无作用。在36℃时，BRL 34915（延迟后）增加了正向钾电流反转电位及更负电位时的外向电流。在200毫秒脉冲期间，峰值钾电流的正常内向整流电流-电压关系变为近乎欧姆定律的关系。BRL 34915激活的电流被格列本脲阻断。数据支持这样的假设，即BRL 34915与缺氧一样，激活心脏中的ATP敏感性钾通道。基于BRL 34915作用的深刻温度敏感性，这种激活可能是间接的，也许是通过调节调节这些通道门控的酶活性来实现的。BRL 34915和格列本脲将是研究ATP敏感性钾通道在正常和异常心脏功能中作用的有价值工具。
