The Effect Of An ATP-sensitive K⁺ Channel Opener- Pinacidil On Myocardial Protection

Cardioplegic arrest during cardiac surgery has traditionally been accomplished through administration of a hyperkalemic cardioplegic solution. However, ventricular dysfunction has been shown to occur after hyperkalemic cardioplegic arrest which may involve alterations in ionic homeostasis and intracellular pH changes. The Langendorff perfusion model and isolated myocyte model of simulated cardioplegic arrest may be useful to determine mechanisms responsible for contractile dysfunction with reperfusion as well as potential strategies to prevent these effects. Adenosine triphosphate (ATP)-sensitive potassium channels(KATP) exist within the myocyte that open in response to reductions in intracellular ATP or ischemia. The protective effects of ischemic preconditioning in regional or global ischemia have been shown to be mediated in part by the KATP channel. Recent studies have also demonstrated that a brief period of KATP channel activation by a potassium channel opener (PCOs) before ischemia improves myocardial function and reduces infarct size with reperfusion. Moreover, KATP channel activationbefore hypothermic, hyperkalemic cardioplegic arrest or used for hyperpolarized cardioplegic arrest improves functional recovery of myocardium. Cardioplegic arrest with simultaneous activation of KATP channels preserves myocyte contractile processes and attenuates the accumulation of intracellular calcium. The role of cellular cation homeostasis in ATP-sensitive K+ channel-induced cardioprotection is poorly understood. As a result of the structural, metabolic and ischemic tolerance differences, clinical myocardial protection strategies and cardioplegic solutions that are effective in adult hearts may be less effective in immature infant or neonatal hearts. In this project we set up two kind experimental models to understand the effects and mechanism of KATP channel opener-Pinacidil. Parti :The purpose of this study is to investigate the effectiveness of pinacidil, an opener of ATP sensitive K+ channels, in protecting myocardium of immature rabbits hearts from ischemic reperfusion injury. Part2:The objectives of the this study are threefold: first, to compare the erfects of cardioplegic arrest through the use of a potassium channel opener (PCO)-supplemented cardioplegia with traditional hyperkalemic cardioplegia on myocyte contractile function; second, to measure intracellular calcium transient in the myocyte with reperfusion ; and third to measure the role of the sarcoplasmic reticulum in the myocyte with reperfusion and calculate the duration of calcium transient evoked by caffeine to demonstrate the role of the Na+-Ca2+ exchanger to better define mechanism of myocyte contractile dysfunction.Part 1Myocardial protection of immature rabbits with an ATP-sensitive K* channel opener pinacidil.Objective: As a result of the structural, metabolic and ischemic tolerance differences, clinical myocardial protection strategies and cardioplegic solutions that are effective in adult hearts may be less effective in immature infant or neonatal hearts. The purpose of this study is to investigate the effectiveness of pinacidil, an opener of ATP sensitive K+ channels, in protecting myocardium of immature rabbits hearts from ischemic reperfusion injury. Methods On modified Langendorff apparatus heart underwent 30 minutes of global normothermic ischemia followed by 30 minutes of reperfusion. 52 isolated hearts of 3-4 weeks old immature rabbits were divided into four groups randomly. During ischemia, three different cardioplegic solutions were administered intermittently by infusion every 15 minutes (20-25ml every time in all groups). Control group (n=13); 16K-cardioplegia group(K group): K-H solution with potassium (16 mmol/L)(n=13); PCO/16K-cardioplegia group (K+P group): K-H solution with potassium (16mmol/L) and pinacidil (50|imol/L)(n=13); PCO/ PCO antagonist/16K-cardioplegia group (K+P+G group): K-H solution with potassium (16mmol/L), pinacidil (50umol/L) and glibenclamide (10jimol/L)(n=13). The pre-ischemic and pos...