Basic fibroblast growth factor and heparin influence coronary arteriolar tone by causing endothelium-dependent dilation

Objective: The strong angiogenic and mitogenic agents acidic and basic fibroblast growth factors (aFGF and bFGF, respectively) share signalling pathways with known vasodilatory agonists. Therefore,we hypothesized that FGF's produce vasoactive responses. We also proposed that heparin would exert a similar action to FGF, because this proteoglycan not only binds to the FGF receptor, but also facilitates the release of FGF from the cardiac extracellular matrix and promotes its binding to a high-affinity receptor. To test these hypotheses, we examined the vasodilatory reactions of coronary arterioles to aFGF, bFGF, and heparin, and the effects of antagonists to nitric oxide synthase (L-NMMA), prostaglandins (indomethacin), ATP-sensitive potassium (K-[ATP]) channels (glibenclamide), FGF and FGF receptors on the vasoactive responses. Methods: Arterioles (70-110 mu m, internal diameter) were dissected from pig hearts and cannulated with micropipettes, Diameter was determined with videomicroscopy in response to bFGF and aFGF in concentrations of 1-100 ng/ml and to heparin (5-200 U/ml). Results: Basic FGF, but not aFGF, caused dose-dependent vasodilation with a maximum of 61 +/- 4%. Relaxation to bFGF was antagonized by pretreatment with L-NMMA, but was not affected by pretreatment with indomethacin or glibenclamide. Heparin caused dose-dependent vasodilation with a maximum of 100 +/- 3% which was partially blocked by either L-NMMA or glibenclamide, but not by indomethacin. Furthermore, the effect of bFGF could be significantly blocked by pretreatment with an FGF receptor antibody as well as with a monoclonal antibody against FGF. Pretreatment with both antibodies significantly inhibited also the effect of heparin. Conclusions: These results indicate that bFGF and heparin cause vasodilation of coronary arterioles via an increase in NO production and heparin additionally by other mechanisms such as by activating K[(ATP)] channels. Furthermore, the effect of heparin is partially mediated via FGF and FGF receptors. We therefore speculate that both substances may be involved in the regulation of coronary microvascular tone acting partially through the same signalling mechanisms.