Role of cardiac ATP-sensitive K+ channels induced by angiotensin II type 1receptor antagonist on metabolism, contraction and relaxation in ischemia-reperfused rabbit heart

The role of cardiac adenosine triphosphate-sensitivs K+ (KATP) channels ind uced by angiotensin II type 1 (ATI) receptor antagonist, CV-11974, on myoca rdial metabolism and contraction during ischemia, and reperfusion by the ph osphorus 31-nuclear magnetic resonance in Langendorff-perfused rabbit heart s was investigated. After 20 min of continuous normothermic global ischemia , 30 min of postischemic reperfusion was carried out. CV-111974 ith or with out the KATP channel blocker, glibenclamide, or the bradykinin B-2 receptor antagonist, D-Arg[Hyp", 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 sy stolic developed pressure, left ventricular end-diastolic pressure (LVEDP), and coronary flow were measured. Twenty-eight hearts were divided into 4 e xperimental groups consisting of 7 hearts each. Group I consisted of contro ls, Group II perfused with CV-11974 (10(-6) mol/L), Group III perfused with CV-11974 (10(-6) mol/L)d in combination with glibenclamide (10(-6) mol/L), and Group IV perfused with CV-11974 (10(-6) mol/L) in combination with D-A rg[Hyp(3),D-Phe(7)]braclykinin (10(-6) mol/L), Group II showed a significan t inhibition of the decrease in ATP during ischemia and reperfusion compare d with Group I (p<0.01), being 42<plus/minus>3% and 19 +/-4% at ischemia, 6 9 +/-3% and 47 +/-4% at reperfusion in Group II and Group I, respectively. Group IT also showed a significant inhibition of the increase in LVEDP duri ng ischemia and reperfusion compared with Group I (p<0.01), being 13<plus/m inus>4 mmHg and 52 +/-8 mmHg at ischemia, 8 +/-2 mmHg and 26 +/-5 mmHg at r eperfusion in Group II and Group I, respectively. However, Group III did no t inhibit the decrease in ATP and the increase in LVEDP during ischemia and reperfusion. Group IV also showed no inhibition of the aforementioned para meters during the same period. These results suggest that CV-11974 has a si gnificant beneficial effect for improving myocardial energy metabolism and relaxation during both myocardial ischemia and reperfusion, which is provid ed by KATP channels and bradykinin B2 receptor. The cardioprotective qualit y of the AT1 receptor antagonist is caused by the KATP channels that are me diated by the bradykinin B2 receptor.