The risk of myocardial stunning is decreased concentration-dependently by K ATP channel activation with nicorandil before high K + cardioplegia

Abstract

Background: Drug-induced opening of the adenosine triphosphate-sensitive potassium channel (K ATP) during hypoxia and/or ischemia, achieved significant myocardial protection in several in vitro and in vivo models. Pretreatment with K ATP openers simulated preconditioning and thus enhanced recovery from ischemia. We have demonstrated that the risk of hypoxia-induced myocardial stunning is reversed by K ATP activation with 1 mmol/l nicorandil before cold cardioplegic arrest. Whether lower concentrations were effective is not known. Methods: In guinea pig papillary muscle preparations contracting isometrically (driven at 1600 ms cycle), nicorandil was superfused (15 min) either 1 μmol/l ( n = 4), 30 μmol/l ( n = 4), 100 μmol/l ( n = 4), or 1 mmol/l ( n = 8) in Tyrode's solution (oxygen content 16 ml/l, 37 °C, 5 ml/min). Controls were superfused with saline (Tyrode's solution; n = 8). A group containing vehicle (DMSO 1%, n = 8) was also studied. In four preparations the K ATP channel blocker glibenclamide 1 μmol/l was given before nicorandil 1 mmol/l. Then, long-lasting (120 min) but moderately hypoxic (oxygen content 5 ml/l: 31% of Tyrode's solution) superfusion with hypothermic (20 °C) high K + (16 mmol/l) cardioplegic solution (5 ml/min) was performed. Recovery of contractility was evaluated after further 60 min of reoxygenation with Tyrode's solution based on DT TPT (developed tension divided by time to peak tension) as percent of prehypoxia basal values (% DT TPT60 ). DT TPT was also studied following 15 min of inotropic stimulation with dobutamine 10 μmol/l (% DT TPT75 ). To assess the risk of stunning, we used a multivariate linear model by all possible subsets analysis (BMDP-9R) aimed at predicting both % DT TPT60 and % DT TPT75 (as continuous dependent variables). Results: During cardioplegia induction, time to arrest (TTA) was (mean ± S.D.) 103 ± 48s in control preparations which had poor recovery of contractility (stunning) after reoxygenation (% DT TPT60 : 71 ± 20%; % DT TPT75 : 443 ± 272%). Nicorandil (1 μmol/l-1 mmol/l) abbreviated TTA concentration-dependently (163 ± 74, 149 ± 103, 82 ± 20, and 56 ± 27s) and improved both % DT TPT60 (63 ± 9, 78 ± 17, 87 ± 13, and 98 ± 11%) and % DT TPT75 (587 ± 333, 619 ± 107, 971 ± 301, and 666 ± 400%). Glibenclamide reversed the effects of nicorandil 1 mmol/l (TTA: 165 ± 30 s, P < 0.01; % DT TPT60 : 43 ± 12, P < 0.01; % DT TPT75 : 272 ± 147, P < 0.05). Multivariate prediction of myocardial stunning at both 60 and 75 min reoxygenation showed that nicorandil (30 μmol/l–1 mmol/l) was a significant ( P < 0.001) protectant whereas glibenclamide was a significant risk factor ( P = 0.009). It is unclear whether negative inotropic effects of nicorandil (% DT TPT at the end of pretreatment) was mechanistically related to reduced risk of stunning since contribution was seen only to predict % DT TPT75 ( t = −3.24, P = 0.003) whereas a positive association was observed with % DT TPT60 ( t = 1.89, P = 0.068). Conclusion: Pretreatment with nicorandil concentration-dependently enhanced the cardioprotective effect of hypothermic high K + cardioplegia. The risk of myocardial stunning was decreased by K ATP opening with nicorandil and increased by K ATP block with glibenclamide. Inotropic stimulation with dobutamine might unravel the role of negative inotropic effect of K ATP opening as a contributory factor to explain the efficacy of nicorandil in our model.