Changes in the vascular responses to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in chronically ischemic myocardium have not been investigated. Ameroid constrictors were placed on the proximal left circumflex (LCX) artery of seven Yorkshire pigs. Seven to nine weeks later, myocardial blood flow in the collateral-dependent LCX region was reduced, compared with that in the normally perfused left anterior descending (LAD) region. Both growth factors elicited significant relaxations of coronary microvessels. Relaxations to both VEGF and bFGF were inhibited in the presence of either NG-nitro-L-arginine or genistein, suggesting that the relaxations are through the tyrosine kinase-mediated release of endothelium-derived nitric oxide. Microvascular relaxations to both VEGF or bFGF were significantly greater in vessels harvested from the collateral-perfused LCX region, compared with those taken from the normally perfused LAD region. However, relaxation to the endothelium-dependent vasodilator ADP, which does not operate through a tyrosine kinase receptor, was reduced in the collateral-perfused region, compared with the normally perfused territory, suggesting a possible link of tyrosine kinase to the enhanced relaxations to VEGF and bFGF in collateral-perfused coronary microvessels. Northern analysis showed increased expression for both VEGF receptors (flk-1, flt-1) as well as the bFGF receptor 1 (FGFR-1) in the collateral-perfused region compared with that in the normally perfused region. This suggests that the increased relaxation responses to VEGF and bFGF in the ischemic myocardium may be related to increased gene expression of the respective tyrosine kinase receptors.