Sugimoto S, Puddu P E, Monti F, Schiariti M, Campa P P, Marino B
Department of Cardiac Surgery, University of Rome La Sapienza, Italy.
J Thorac Cardiovasc Surg. 1994 Sep;108(3):455-66.
We hypothesized that pretreatment with the potassium channel opener nicorandil might enhance myocardial protection achieved by cold (20 degrees C) high-potassium (16 mmol/L) cardioplegia (5 ml/min) during long-duration (120 minutes) myocardial hypoxia (average oxygen content 5.4 ml/dl). We tested a 15-minute infusion of nicorandil (1 mmol/L) given only before (group A, n = 8) or before and during cardioplegia (group B, n = 8) in guinea pig papillary muscle preparations contracting isometrically while stimulated (4 mA, 2 msec) at 1600 msec cycle length. Nicorandil was significantly negative inotropic before cardioplegia and shortened significantly action potential duration. During cardioplegia, time to arrest of contraction was shortened from 145 +/- 28 seconds (mean +/- standard error) in the vehicle group (dimethyl sulfoxide 1:100; n = 8) to 56 +/- 10 seconds (p < 0.02) and 68 +/- 5 seconds (p < 0.05) in groups A and B, respectively. Recovery of developed tension at 60 minutes of normothermic reoxygenation (expressed as percent of prehypoxia basal value) was ameliorated from 54% +/- 6% (vehicle group) to 92% +/- 4% (group A, p < 0.01) and to 119% +/- 19% (group B, p < 0.01). The specific potassium channel blocker glibenclamide (glib: 1 mumol/L, n = 8) prolonged action potential duration and was without effect on time to arrest. On reoxygenation, the glib group had prolonged time to half relaxation (versus group A, p < 0.02) and the worst percent developed tension at 60 minutes (40% +/- 4%). In the overall study, time to arrest and percent developed tension at 60 minutes were inversely correlated (r = -0.45, p < 0.01). Arrhythmias were never observed. Multivariate analysis showed that pretreatment with nicorandil (with or without drug adjunct to cardioplegic solution) was a significant factor (r2 = 0.65, p = 0.0001) to influence reoxygenation-mediated recovery of mechanical function. Neither the negative inotropic effect of nicorandil before cardioplegia nor its abbreviating action on time to arrest during cardioplegia was contributory to explain recovery of function on reoxygenation. In subgroup analysis, negative inotropism and the shortening of action potential duration were contributory factors. These data suggest that nicorandil pretreatment activates potassium channels and enhances the myocardial protection provided by cold cardioplegia an effect, which is evident after a long hypoxic period, late on reoxygenation.
我们假设，在长时间（120分钟）心肌缺氧（平均氧含量5.4毫升/分升）期间，用钾通道开放剂尼可地尔预处理可能会增强冷（20℃）高钾（16毫摩尔/升）心脏停搏液（5毫升/分钟）所实现的心肌保护作用。我们在豚鼠乳头肌标本中进行了测试，该标本在1600毫秒的周期长度下等长收缩并受到刺激（4毫安，2毫秒），仅在心脏停搏前（A组，n = 8）或在心脏停搏前及停搏期间（B组，n = 8）给予15分钟的尼可地尔输注（1毫摩尔/升）。在心脏停搏前，尼可地尔具有显著的负性肌力作用，并显著缩短动作电位时程。在心脏停搏期间，收缩停止时间从溶媒组（二甲亚砜1:100；n = 8）的145±28秒（平均值±标准误）分别缩短至A组的56±10秒（p < 0.02）和B组的68±5秒（p < 0.05）。在常温复氧60分钟时，发展张力的恢复（以缺氧前基础值的百分比表示）从溶媒组的54%±6%改善至A组的92%±4%（p < 0.01）和B组的119%±19%（p < 0.01）。特异性钾通道阻滞剂格列本脲（格列：1微摩尔/升，n = 8）延长动作电位时程，且对收缩停止时间无影响。在复氧时，格列组达到半松弛的时间延长（与A组相比，p < 0.02），且在60分钟时发展张力的百分比最差（40%±4%）。在整个研究中，收缩停止时间与60分钟时发展张力的百分比呈负相关（r = -0.45, p < 0.01）。未观察到心律失常。多变量分析表明，用尼可地尔预处理（无论心脏停搏液中是否添加药物）是影响复氧介导的机械功能恢复的一个重要因素（r2 = 0.65, p = 0.0001）。尼可地尔在心脏停搏前的负性肌力作用及其在心脏停搏期间对收缩停止时间的缩短作用均无助于解释复氧时的功能恢复。在亚组分析中，负性肌力作用和动作电位时程的缩短是促成因素。这些数据表明，尼可地尔预处理可激活钾通道并增强冷心脏停搏液提供的心肌保护作用，这种作用在长时间缺氧期后、复氧后期很明显。
