ACTIONS OF EPOXYGENASE METABOLITES ON THE PREGLOMERULAR VASCULATURE

Epoxygenase metabolites of arachidonic acid are produced by the kidney and have been implicated in the control of renal blood flow, This stu dy examined the preglomerular actions of various epoxyeicosatrienoic a cids (EET). By use of the in vitro blood-perfused juxtamedullary nephr on preparation, interlobular and afferent arteriolar diameter response s to 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET were determined. Diame ters of interlobular and afferent arterioles preconstricted with 0.5 m u M norepinephrine averaged 24 +/- 1 mu m (N = 27) and 17 +/- 1 mu m ( N = 32), respectively, at a renal perfusion pressure of 100 mm Hg. Sup erfusion with 0.01 to 100 nM 11,12-EET caused graded increases in diam eters of the interlobular and afferent arterioles. At a dose of 100 nM , 11,12-EET increased the diameters of the interlobular and afferent a rterioles by 18 +/- 2% (N = 10) and 20 +/- 3% (N = 9), respectively. T he vasodilatory response to 11,12-EET was stereoselective because 11,1 2(R,S)-EET but not 11,12(S,R)-EET increased the diameters of the inter lobular and afferent arterioles. 14,15-EET had a much smaller effect a nd increased the diameters of the these vessels by 10%; 8,9-EET did no t significantly affect vascular diameters. In contrast, 5,6-EET constr icted the interlobular and afferent arterioles by 16 +/- 3% (N = 6) an d 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 mu M. The vasodilatory r esponse to 11,12-EET was not affected by removal of the endothelium or by inhibition of cyclooxygenase with indomethacin. In contrast, the v asoconstrictor response to 5,6-EET was abolished by both removal of th e endothelium or cyclooxygenase inhibition, The thromboxane/enderopero xide receptor inhibitor, SQ 29,548, resulted in a 60% attenuation of t he afferent arteriolar vasoconstriction to 5,6-EET, These results indi cate that the preglomerular vasoconstriction to 5,6-EET is cyclooxygen ase dependent and requires an intact endothelium, whereas the vasodila tion to 11,12-EET is stereoselective and is the result of direct actio n of the epoxide on the preglomerular vascular smooth muscle.