An increased release of the potent vasoconstrictor endothelin (ET) may play a role in the development of myocardial stunning. We, therefore, hypothesized that blockade of ET with either monoclonal antibodies against ET-1 and ET-3 (a-ET1/3-ab) or with the ET(A) receptor antagonist BQ123 would improve the reduction in myocardial blood flow (MBF; H2 clearance) and fractional wall thickening (FT; pulsed Doppler) after repetitive ischemia/reperfusion in an in situ perfused rat model. Under baseline conditions, ET-1 dose dependently decreased MBF and increased mean arterial blood pressure. FT and heart rate were unaltered. Pretreatment with both a-ET1/3-ab or BQ123 effectively blocked the effects of ET. Following repetitive ischemia, MBF was significantly reduced from 3.5 +/- 0.4 to 2.1 +/- 0.3 ml x min-1 x g-1 (p < 0.05) and FT from 16.2 +/- 1.7 to 9.4 +/- 1.1% in the control group (p < 0.05). Pretreatment with either antibodies did not significantly improve the attenuation in MBF and FT at the end of the ischemic protocol. These results indicate that inhibition of ET-1 by monoclonal antibodies or by ET(A) receptor blockade does not influence the decrease in MBF and FT in repetitive ischemia/reperfusion. We, therefore, propose that ET is not a major determinant in the development of myocardial stunning.