The Interaction between Endothelium-Derived Relaxing Factor (EDRF) and Eicosanoids in the Regulation of the Mesenteric Microcirculation

Abstract

Locally produced eicosanoids and endothelium-derived factors are believed to be the mediators of vascular tone of various vascular beds including the mesentery. Using a small vessel isometric myograph which allows direct measurement of microvascular reactivity, the interaction of eicosanoids and endothelium-derived relaxing factor (EDRF) in regulating vascular tone of mesenteric microcirculation of the rat was characterized. The microvascular response to various vasoactive agents before and after inhibition of prostacyclin production with indomethacin (INDO, 5 μM) and inhibition of EDRF synthesis with Nω-nitro-dcl026;-arginine methyl ester (dcl026;-NAME, 50 μM) was compared. Analysis of dose-response curves for prostaglandin F2α (PGF2α), U46619, a stable thromboxane analog, and norepinephrine (NE) after pretreatment with INDO demonstrated that inhibition of endogenous eicosanoids significantly attenuated the vasoconstrictor response to PGF2α and U46619 but not to NE. Inhibition of EDRF synthesis with dcl026;-NAME potentiated the vasoconstrictor response to PGF2α, U46619, and NE. These results suggest that EDRF acts as the primary mediator of vasodilator tone in the mesenteric microcirculation rather than vasodilator cyclooxygenase products such as prostacyclin. It also appears that the vasoconstrictor action of PGF2α and U46619 may be mediated by a release of an endogenous indomethacin-sensitive factor.