Role of Cardiac ATP-Sensitive K^+ Channels Induced by Angiotensin II Type 1 Receptor Antagonist on Metabolism, Contraction and Relaxation in Ischemia-Reperfused Rabbit Heart

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The role of cardiac adenosine triphosphate-sensitive K^+ (K_<ATP>) channels induced by angiotensin II type 1 (AT1) receptor antagonist, CV-11974, on myocardial metabolism and contraction during ischemia, and reperfusion by the phosphorus 31-nuclear magnetic resonance in Langendorff-perfused rabbit hearts was investigated. After 20 min of continuous normothermic global ischemia, 30 min of postischemic reperfusion was carried out. CV-11974 with or without the K_<ATP> channel blocker, glibenclamide, or the bradykinin B_2 receptor antagonist, _D-Arg- [Hyp^3, _D-Phe^7]bradykinin, was administered 40 min prior to the global ischemia. Adenosine triphosphate (ATP), creatine phosphate (PCr), inorganic phosphate (Pi), intracellular pH (pHi), left ventricular systolic developed pressure, left ventricular end-diastolic pressure (LVEDP), and coronary flow were measured. Twenty-eight hearts were divided into 4 experimental groups consisting of 7 hearts each. Group I consisted of controls, Group II perfused with CV-11974 (10^<-6>mol/L), Group III perfused with CV-11974 (10^<-6>mol/L) in combination with glibenclamide (10^<-6>mol/L), and Group IV perfused with CV-11974 (10^<-6>mol/L) in combination with _D-Arg- [Hyp^3, _D-Phe^7]bradykinin (10^<-6>mol/L). Group II showed a significant inhibition of the decrease in ATP during ischemia and reperfusion compared with Group I (p<0.01), being 42±3% and 19±4% at ischemia, 69±3% and 47±4% at reperfusion in Group II and Group I, respectively. Group II also showed a significant inhibition of the increase in LVEDP during ischemia and reperfusion compared with Group I (p<0.01), being 13±4 mmHg and 52±8 mmHg at ischemia, 8±2 mmHg and 26±5 mmHg at reperfusion in Group II and Group I, respectively. However, Group III did not inhibit the decrease in ATP and the increase in LVEDP during ischemia and reperfusion. Group IV also showed no inhibition of the aforementioned parameters during the same period. These results suggest that CV-11974 has a significant beneficial effect for improving myocardial energy metabolism and relaxation during both myocardial ischemia and reperfusion, which is provided by K_<ATP> channels and bradykinin B_2 receptor. The cardioprotective quality of the AT1 receptor antagonist is caused by the K_<ATP> channels that are mediated by the bradykinin B_2 receptor.
社団法人日本循環器学会の論文
2001-04-20

Role of Cardiac ATP-Sensitive K^+ Channels Induced by Angiotensin II Type 1 Receptor Antagonist on Metabolism, Contraction and Relaxation in Ischemia-Reperfused Rabbit Heart

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