Haruhiko Ishioka

The role of ATP-sensitive potassium channels in the mechanism of ischemic preconditioning.

We clarified the role of K(ATP) channels in the mechanism of ischemic preconditioning by using K(ATP) channel opener, nicorandil, and K(ATP) channel inhibitor, glibenclamide. Forty anesthetized dogs were divided into five groups: (a) control (C), (b) ischemic preconditioning (PC), (c) intravenous infusion of nicorandil before PC (Ni), (d) glibenclamide pretreated with PC (Gl + PC), and (e) glibenclamide pretreated with Ni (Gl + Ni). All groups were followed by 60-min ischemia and 60-min reperfusion and analyzed by the biochemical procedures. At the end of 60-min reperfusion, percentage of segment shortening in C indicated paradoxic bulging. This value was significantly recovered in PC and Ni, but it was still negative in Gl + PC and Gl + Ni. Ca2+ -adenosine triphosphatase (ATPase) activity of sarcoplasmic reticulum (SR) was significantly decreased in C. In PC and Ni, this activity was significantly maintained; however, in Gl + PC and Gl + Ni, it was similar to that in C. State III respiration of mitochondria showed similarity to the changes in SR. These results indicated that the K(ATP) channel opener enhanced the effects of ischemic preconditioning, and its blockade abolished these phenomena. We conclude that the ATP-sensitive potassium channel may play one of key roles in the mechanisms of ischemic preconditioning in the dog model.

Ultrastructural and biochemical studies of ischemic preconditioning using an adenosine receptor blocker and an ATP-sensitive K channel opener

The effect of preconditioning (PC) on acute ischemic myocardial injury was investigated in an openchest dog model. Preconditioned dogs received four 5-min occlusions of the left anterior descending coronary artery (LAD), each separated by 10 min of reperfusion. Four groups were used to assess the effect: non-PC group (G-1), PC group (G-2), 8-phenyltheophylline-(adenosine receptor blocker) infused PC group (G-3), and nicorandil- (ATP-sensitive K-channel opener) infused PC group (G-4). The LAD was occluded for 60 min, followed by 60 min of reperfusion in all dogs. The rate of ultrastructural myocardial severe injury was 26% in G-1, 0% in G-2, 5% in G-3, and 0% in G-4. Biochemical analayses also indicated higher values of myocardial contractile function in G-2 and G-4 than G-1 and G-3. These data suggest that the adenosine receptor and K channel may play a key role in PC.

Pathophysiological Behavior of the Myocardium in Acute Ischemia and Reperfusion, with Special Emphasis on the Sarcoplasmic Reticulum

The myocardium under severe ischemia and reperfusion exhibits four types of different pathophysiologic behaviors: coagulation necrosis, stunning, ischemic preconditioning, and reperfusion injury. This chapter describes these changes in the postischemic myocardium in relation to the length of ischemia. Canine hearts were made ischemic by occludmg the left anterior descending coronary artery (LAD), and the sarcoplasmic reticulum (SR) from the ischemia-reperfused myocardium was analyzed. In permanent occlusion of the LAD, Ca2+-ATPase activity of the SR was reduced simultaneously with the degradation of the major ATPase protein in ischemia for 20 to 30 minutes. In the stunned myocardium, with occlusion of the LAD for 15 minutes and reperfusion, long-term reduction in the activity of the SR was noted simultaneously with a reduction in the percent of segment shortening, but without degradation of the ATPase protein of the SR. In the preconditioned myocardium, in which the LAD was occluded four times for five minutes each prior to LAD occlusion for 60 minutes and reperfusion, both ATPase activity and the SR ATPase protein were preserved In reperfusion of the LAD after occlusion for 10 to 30 minutes, reduction in Ca2+-ATPase activity and degradation of the ATPase protein occurred earlier, simultaneously with generation of free radicals, suggesting reperfusion injury. We conclude that pathophysiologic behaviors of the postischemic myocardium proceed in quite different ways depending upon the length of ischemia and will only be fully understood in the light of studies on ischemia and reperfusion of the heart muscle.

Effects of Catecholamine and Amrinone on the Metabolism of Noninfarcted Myocardium in Cardiogenic Shock

We investigated the effects of catecholamine and amrinone (AMR) on the metabolism of noninfarcted myocardium (NIM) during heart failure in acute myocardial infarction. Acute myocardial ischemia was induced by left circumflex coronary artery ligation on dogs divided into two groups: in the C group, left ventricular pressive (LVP) remained at >70% and in the S group, LVP decreased to <70% of preligation values. In part of the S group, 10 μg/kg/min of dopamine (DOA) or dobutamine (DOB), or 60μg/kg/min of AMR, were given intravenously beginning 90 min after ligation. At the end of 120 min of ischemia, mitochondria were extracted from NIM, and respiratory and electron transport system enzyme activities were measured. In the DOA and DOB groups, LVP, myocardial blood flow, cardiac output, and max LV dp/dt recovered significantly. In the AMR group, in spite of LVP reduction, other hemodynamic parameters increased. In the S group, state III respiration, complex I, and DNP-ATPase activities in NIM decreased to 62%, 65%, and 68% of preligaton levels, respectively. These values improved markedly with DOA, DOB, and AMR treatments. Electron microscopy showed swelling and fusion of mitochondria in the S group. These results indicate that catecholamine and AMR improve energy production in NIM and ultimately improve cardiac function.

Metabolic Changes in Nonischemic Myocardium During Pump Failure

Metabolic changes in the nonischemic myocardium after acute myocardial infarction in canine hearts were studied. Ca2+-ATPase activity and the major ATPase protein of the sarcoplasmic reticulum, tissue levels of ATP, mitochondrial respiratory, and complex I activities were decreased in the noninfarcted zone in proportion to heart function. It is suggested that recovery of these functions may be important in any treatment of pump failure.