Endothelin-1 (ET-1) influences the electrical activity of the heart by causing arrhythmias associated with lengthening of the QT interval in the electrocardiogram. Recent results from our laboratory have shown a primary role for a high plasma glucose concentration in determining cardiac QT prolongation. Since high glucose up-regulates the ET-1 system, the aim of the present study was to determine whether the increase of the QT interval and coronary vascular tone induced by high glucose in the heart involves increased activity of the ET system. Perfusion of isolated hearts with a high glucose concentrations (33.3 mM) prolonged the QT interval significantly and increased coronary perfusion pressure (CPP) ( P<0.01). The increases in the QT interval and CPP induced by high glucose were accompanied by increases in cardiac ET-1 levels, and were significantly reduced by an ET-1 antiserum ( P<0.01). Perfusion of the hearts with the selective ET(A) receptor antagonist FR139317 or with the non-selective ET(A)/ET(B) antagonist SB209670, but not with the selective ET(B) receptor antagonist BQ-788, reduced the glucose-induced QT prolongation. In addition, the increase in cardiac vascular tone, as evidenced by the increase in CPP, induced by high glucose was reversed partially by cardiac perfusion with either the non-selective ET(A)/ET(B) receptor antagonist or the ET(B)-selective BQ-788, whereas the ET(A) antagonist was without effect. By increasing the production of ET-1, a high glucose concentration may activate parallel pathways that contribute to a state of increased vasomotor tone and electrical ventricular instability. Antagonism at cardiac ET receptors could be helpful in these cardiovascular complications of diabetes.