Several studies indicate an interaction between the renin-angiotensin (Ang II) and endothelin (ET) systems in the regulation of vascular tone. Previously we showed that both ET and Ang II exert a vasoconstrictor influence on the coronary resistance vessels of awake normal swine. Here we investigated whether interaction between Ang II and ET exists in coronary resistance vessels at rest and during exercise, using single and combined blockade of the AT₁ and ET_A/ET_B receptors. Furthermore, since both circulating Ang II and ET levels are increased after myocardial infarction (MI), we investigated if the interaction between these systems is altered after MI. In awake healthy swine, the coronary vasodilation in response to ET_A/ET_B receptor blockade in the presence of AT₁ blockade was similar to the vasodilation produced by ET_A/ET_B blockade under control conditions. In awake swine with a 2-3 week old MI, the coronary vasodilator responses to individual AT₁ and ETA/ETB receptor blockade were virtually abolished, despite similar coronary arteriolar AT₁and ET_A receptor expression as compared to normal swine. Unexpectedly, in the presence of AT₁ blockade (which had no effect on circulating ET levels), ET_A/ET_B receptor blockade elicited a coronary vasodilator response. These findings suggest that in normal healthy swine the two vasoconstrictor systems contribute to coronary resistance vessel control in a linear additive manner, i.e. with negligible cross-talk. In contrast, in remodeled myocardium cross-talk between Ang II and ET emerges, resulting in non-linear redundant control of coronary resistance vessel tone.