EFFECTS OF ENDOTHELIN-1 AT PATHOPHYSIOLOGIC CONCENTRATIONS ON CORONARY PERFUSION AND MECHANICAL FUNCTION OF NORMAL AND POSTISCHEMIC MYOCARDIUM

We assess hemodynamic, vascular, and hormonal effects of endothelin-l (ET-1) at pathophysiologic levels on normal and ischemic myocardium. Thirty conscious chronically instrumented dogs were studied before, during, and after a 10-min coronary artery occlusion (CAO) performed either during ET-1 infusion (2.5 ng/kg min, n=15) or during placebo infusion (n=15). ET-1 infusion produced an increase in plasma ET-1 (from 1.3+/-0.1 to 11.5+/-1.1 pM, p<0.0001) during CAO (pathophysiologic value). Left anterior descending artery (LAD) blood flow (measured by Doppler flow probe) decreased similarly during CAO with ET-1 or placebo (p=0.0001, NS, ET-1 vs, placebo). Both endocardial and epicardial blood flows in ischemic regions also decreased (p=0.0001) during CAO but were threefold greater with ET-1 than with placebo (endocardium 42+/-7 vs. 14+/-2 ml/min/100 g, p=0.003). No significant difference in myocardial blood flows between groups was observed in control regions. CAO produced increases (p<0.005) in heart rate (HR), mean aortic pressure (AOP), and ventricular pressures but no change in atrial pressures. The changes in these parameters were comparable in the ET-1 and placebo groups. Despite the greater residual flow during CAO, however, ET-1 decreased the function of the ischemic zone during reperfusion as assessed by systolic shortening (p<0.05). Atrial natriuretic factor (ANF), unchanged during CAO with placebo, increased from 38.3+/-6.1 to 53.3+/-10 pM with ET-1 (p=0.02). Thus, ET-1, at pathophysiologic levels, increases collateral blood flow in ischemic myocardium without affecting perfusion of normal myocardium. It decreases postischemic myocardial recovery and directly stimulates ANF release.