Ito M, Pride H P, Zipes D P
Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis 46202.
Circ Res. 1994 Aug;75(2):379-92. doi: 10.1161/01.res.75.2.379.
To investigate the role of ATP-sensitive K+ channels in modulating the efferent autonomic response following acute myocardial ischemia/infarction, we examined the effects of a blocker (glibenclamide) and an opener (pinacidil) of ATP-sensitive K+ channels on the time course and extent of the attenuation in efferent cardiac sympathetic responsiveness in anesthetized dogs. We measured the effective refractory periods (ERPs) at nonischemic sites basal and apical to the area of myocardial ischemia/infarction in the baseline state and during bilateral stimulation of the ansae subclaviae before and after each drug administration and 5, 30, 60, 120, and 180 minutes after latex injection of a diagonal branch of the left anterior descending coronary artery. Animals received either vehicle (n = 12), glibenclamide (0.3 mg.kg-1, n = 10), pinacidil (0.15 mg.kg-1 + 0.2 mg.kg-1 infusion, n = 10), or a combination of these two drugs (n = 9) intravenously. In another group of dogs receiving just pinacidil (n = 10), an intra-aortic balloon was inflated distal to the renal arteries to prevent pinacidil-induced hypotension. Another group of dogs received either high-dose glibenclamide (0.3 mg.kg-1 + 0.15 mg.kg-1, n = 4), low-dose glibenclamide (0.06 mg.kg-1, n = 4), medium-dose pinacidil (0.03 mg.kg-1 + 0.04 mg.kg-1 infusion, n = 4), or low-dose pinacidil (0.0075 mg.kg-1 + 0.01 mg.kg-1 infusion, n = 4). In all dogs, basal sites exhibited no attenuation of sympathetically induced shortening of the ERP throughout the period of acute myocardial ischemia/infarction. Cumulative attenuation in sympathetic responsiveness (shortening of ERP < or = 2 milliseconds induced by bilateral stimulation of the ansae subclaviae) at nonischemic test sites apical to the area of ischemia/infarction during a 3-hour period was greater in the glibenclamide group (26 of 44 sites, P = .008) and less in the pinacidil (2 of 44 sites, P = .002) and pinacidil-balloon (1 of 48 sites, P < .001) groups compared with the vehicle group (14 of 46 sites). Glibenclamide abolished the protective effect of pinacidil so that 10 of 45 sites had < 2-millisecond shortening during a 3-hour period in the glibenclamide + pinacidil group (P = .018 versus pinacidil group, P = .286 versus vehicle group). Such effects of glibenclamide and pinacidil on sympathetic attenuation were dose dependent. Maintaining the blood glucose level during glibenclamide administration did not affect the sympathetic attenuation after acute coronary artery occlusion.(ABSTRACT TRUNCATED AT 400 WORDS)
为研究ATP敏感性钾通道在调节急性心肌缺血/梗死后传出自主神经反应中的作用，我们在麻醉犬中检测了ATP敏感性钾通道阻滞剂（格列本脲）和开放剂（吡那地尔）对传出性心脏交感反应性衰减的时间进程和程度的影响。我们测量了在基线状态下以及每次给药前后和左前降支冠状动脉对角支注射乳胶后5、30、60、120和180分钟，在双侧刺激锁骨下袢时，心肌缺血/梗死区域基底部和心尖部非缺血部位的有效不应期（ERP）。动物静脉注射溶剂（n = 12）、格列本脲（0.3 mg·kg-1，n = 10）、吡那地尔（0.15 mg·kg-1 + 0.2 mg·kg-1输注，n = 10）或这两种药物的组合（n = 9）。在另一组仅接受吡那地尔的犬（n = 10）中，在肾动脉远端充气主动脉内球囊以防止吡那地尔引起的低血压。另一组犬接受高剂量格列本脲（0.3 mg·kg-1 + 0.15 mg·kg-1，n = 4）、低剂量格列本脲（0.06 mg·kg-1，n = 4）、中剂量吡那地尔（0.03 mg·kg-1 + 0.04 mg·kg-1输注，n = 4）或低剂量吡那地尔（0.0075 mg·kg-1 + 0.01 mg·kg-1输注，n = 4）。在所有犬中，在急性心肌缺血/梗死期间，基底部部位交感诱导的ERP缩短未出现衰减。与溶剂组（46个部位中的14个）相比，在缺血/梗死区域心尖部的非缺血测试部位，格列本脲组在3小时内交感反应性的累积衰减（双侧刺激锁骨下袢引起的ERP缩短≤2毫秒）更大（44个部位中的26个，P = 0.008），吡那地尔组（44个部位中的2个，P = 0.002）和吡那地尔-球囊组（48个部位中的1个，P < 0.001）更小。格列本脲消除了吡那地尔的保护作用，因此在格列本脲 + 吡那地尔组中，45个部位中有10个在3小时内缩短<2毫秒（与吡那地尔组相比P = 0.018，与溶剂组相比P = 0.286）。格列本脲和吡那地尔对交感衰减的这种作用是剂量依赖性的。在给予格列本脲期间维持血糖水平并不影响急性冠状动脉闭塞后的交感衰减。（摘要截短至400字）
