ELEVATED RENOVASCULAR TONE IN YOUNG SPONTANEOUSLY HYPERTENSIVE RATS -ROLE OF CYTOCHROME-P-450

The present study examined the role of cytochrome P-450 metabolites of arachidonic acid in elevating renal vascular resistance in young spon taneously hypertensive rats (SHR). Differences in vascular tone were a ssessed in the preglomerular vasculature of 3- to 4-week-old prehypert ensive SHR (n=11) and normotensive Wistar-Kyoto (WKY, n=10) and Wistar -Lewis (n=10) rats. Pressure-diameter relations to changes in renal pe rfusion pressure were compared using the juxtamedullary nephron microv ascular preparation perfused in vitro with a physiological salt soluti on. At a pressure of 60 mm Hg, the basal diameters of the interlobular arteries and proximal and distal afferent arterioles of the SHR avera ged 43 +/- 2, 17 +/- 0.3, and 11-0.4 mum, respectively. The diameters of the interlobular arteries and afferent arterioles were 9% to 14% sm aller than those of corresponding vessels in WKY and Wistar-Lewis rats . Addition of P-450 inhibitors, ketoconazole (100 mumol/L) or 7-ethoxy resorufin (1 mumol/L), to the perfusate dilated the afferent arteriole of SHR by 7% to 12%, whereas it increased the diameter by only 0% to 6% in control rats and significantly reduced the differences in the pr essure-diameter relation in the preglomerular vasculature of SHR and c ontrol rats. Inhibitors of P-450 eliminated the contractile response o f afferent arterioles to increases in renal perfusion pressure in all three groups. Removal of calcium from the perfusate eliminated differe nces in the diameters of the preglomerular vasculature in SHR and norm otensive rats. Renal P-450 activities in SHR and normotensive rats wer e compared by incubating cortical microsomes with [C-14]arachidonic ac id, and the products were separated by reversed-phase high-performance liquid chromatography. The production of the primary metabolite, 20-h ydroxyeicosatetraenoic acid, was significantly greater in SHR than in WKY rats, whereas the production of 11,12-epoxyeicosatrienoic acid was greater in WKY rats than in SHR and Wistar-Lewis rats. These observat ions indicate that cytochrome P-450 metabolites of arachidonic acid en hance preglomerular vascular tone in juxtamedullary nephrons of young SHR, which may contribute to the resetting of the pressure-natriuretic relation.