Actions of epoxygenase metabolites on the preglomerular vasculature.

Abstract

Epoxygenase metabolites of arachidonic acid are produced by the kidney and have been implicated in the control of renal blood flow. This study examined the preglomerular actions of various epoxyeicosatrienoic acids (EET). By use of the in vitro blood-perfused juxtamedullary nephron preparation, interlobular and afferent arteriolar diameter responses to 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET were determined. Diameters of interlobular and afferent arterioles preconstricted with 0.5 microM norepinephrine averaged 24 +/- 1 microns (N = 27) and 17 +/- 1 microns (N = 32), respectively, at a renal perfusion pressure of 100 mm Hg. Superfusion with 0.01 to 100 nM 11,12-EET caused graded increases in diameters of the interlobular and afferent arterioles. At a dose of 100 nM, 11,12-EET increased the diameters of the interlobular and afferent arterioles by 18 +/- 2% (N = 10) and 20 +/- 3% (N = 9), respectively. The vasodilatory response to 11,12-EET was stereoselective because 11,12(R,S)-EET but not 11,12(S,R)-EET increased the diameters of the interlobular and afferent arterioles. 14,15-EET had a much smaller effect and increased the diameters of the these vessels by 10%; 8,9-EET did not significantly affect vascular diameters. In contrast, 5,6-EET constricted the interlobular and afferent arterioles by 16 +/- 3% (N = 6) and 21 +/- 3% (N = 7), respectively. The corresponding diols, 5,6-DIHETE and 11,12-DIHETE, had no effect on diameters of the interlobular and afferent arterioles at concentrations up to 1 microM. The vasodilatory response to 11,12-EET was not affected by removal of the endothelium or by inhibition of cyclooxygenase with indomethacin. In contrast, the vasoconstrictor response to 5,6-EET was abolished by both removal of the endothelium or cyclooxygenase inhibition. The thromboxane/ enderoperoxide receptor inhibitor, SQ 29,548, resulted in a 60% attenuation of the afferent arteriolar vasconstriction to 5,6-EET. These results indicate that the preglomerular vasoconstriction to 5,6-EET is cyclooxygenase dependent and requires an intact endothelium, whereas the vasodilation to 11,12-EET is stereoselective and is the result of direct action of the epoxide on the preglomerular vascular smooth muscle.