Cardioprotection from ischemia and reperfusion injury by an endothelin A-receptor antagonist in relation to nitric oxide production

It has previously been shown that endothelin (ET)receptor antagonists prote ct the myocardium from ischemia and reperfusion (I/R) injury. The mechanism behind this effect is unclear. The aim of this study was to elucidate the possible interaction between ETA-receptor antagonism and nitric oxide (NO) during VR. Anesthetized pigs were subjected to 45-min ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. V ehicle (n = 7), the ETA-receptor antagonist LU 135252 (LU; 0.1 mg/kg, n = 7 ), the combination of LU and the NO precursor L-arginine (15 mg/kg, n = 7; LU + L-arg), the NO synthase inhibitor N-G-monomethyl-L-arginine (L-NMMA; 0 .2 mg/kg, n = 6), or the combination of LU and L-NMMA (LU + L-NMMA; n = 6) were injected into the LAD during the last 10 min of ischemia and the first 5 min of reperfusion. There were no significant differences in coronary fl ow, pulmonary capillary wedge pressure, mean arterial pressure, or heart ra te between the groups before ischemia or at the end of reperfusion. The are a at risk was similar in all five groups. The infarct size of the vehicle g roup was 79 +/- 6% of the area at risk. LU and LU + L-arginine (L-arg) redu ced the infarct size to 39 +/- 6% and 35 +/- 8%, respectively (p < 0.001 vs . vehicle). L-NMMA completely prevented the infarct-limiting effect of LU. Thus the infarct size in the LU + L-NMMA group was 83 +/- 4% (p < 0.001 vs. LU alone); L-NMMA did not affect infarct size per se (79 +/- 4%). ET Immun oreactivity increased threefold in the IIR myocardium of the vehicle group. The increase in ET immunoreactivity was significantly attenuated in the LU and LU + L-arg groups (p < 0.001), but not in the groups given L-NMMA or L U + L-NMMA. In conclusion, ETA-receptor blockade results in cardioprotectio n and attenuation of the increase in myocardial ET levels after I/R. Both e ffects were inhibited by NO synthase blockade, suggesting that they are dep endent on maintained production of NO.