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 signall ing pathways with known vasodilatory agonists. Therefore,we hypothesiz ed that FGF's produce vasoactive responses. We also proposed that hepa rin would exert a similar action to FGF, because this proteoglycan not only binds to the FGF receptor, but also facilitates the release of F GF from the cardiac extracellular matrix and promotes its binding to a high-affinity receptor. To test these hypotheses, we examined the vas odilatory reactions of coronary arterioles to aFGF, bFGF, and heparin, and the effects of antagonists to nitric oxide synthase (L-NMMA), pro staglandins (indomethacin), ATP-sensitive potassium (K-[ATP]) channels (glibenclamide), FGF and FGF receptors on the vasoactive responses. M ethods: Arterioles (70-110 mu m, internal diameter) were dissected fro m pig hearts and cannulated with micropipettes, Diameter was determine d 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 no t 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. H eparin caused dose-dependent vasodilation with a maximum of 100 +/- 3% which was partially blocked by either L-NMMA or glibenclamide, but no t by indomethacin. Furthermore, the effect of bFGF could be significan tly blocked by pretreatment with an FGF receptor antibody as well as w ith a monoclonal antibody against FGF. Pretreatment with both antibodi es significantly inhibited also the effect of heparin. Conclusions: Th ese results indicate that bFGF and heparin cause vasodilation of coron ary arterioles via an increase in NO production and heparin additional ly by other mechanisms such as by activating K[(ATP)] channels. Furthe rmore, the effect of heparin is partially mediated via FGF and FGF rec eptors. We therefore speculate that both substances may be involved in the regulation of coronary microvascular tone acting partially throug h the same signalling mechanisms.