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 spontaneously hypertensive rats (SHR). Differences in vascular tone were assessed in the preglomerular vasculature of 3- to 4-week-old prehypertensive SHR (n=11) and normotensive Wistar-Kyoto (WKY, n=10) and Wistar-Lewis (n=10) rats. Pressure-diameter relations to changes in renal perfusion pressure were compared using the juxtamedullary nephron microvascular preparation perfused in vitro with a physiological salt solution. At a pressure of 60 mm Hg, the basal diameters of the interlobular arteries and proximal and distal afferent arterioles of the SHR averaged 43±2, 17±0.3, and 11±0.4 μm, respectively. The diameters of the interlobular arteries and afferent arterioles were 9% to 14% smaller than those of corresponding vessels in WKY and Wistar-Lewis rats. Addition of P-450 inhibitors, ketoconazole (100 μmol/L) or 7-ethoxyresorufin (1 μmol/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 pressure-diameter relation in the preglomerular vasculature of SHR and control rats. Inhibitors of P-450 eliminated the contractile response of afferent arterioles to increases in renal perfusion pressure in all three groups. Removal of calcium from the perfusate eliminated differences in the diameters of the preglomerular vasculature in SHR and normotensive rats. Renal P-450 activities in SHR and normotensive rats were compared by incubating cortical microsomes with [¹⁴C]arachidonic acid, and the products were separated by reversed-phase high-performance liquid chromatography. The production of the primary metabolite, 20-hydroxyeicosatetraenoic 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 observations indicate that cytochrome P-450 metabolites of arachidonic acid enhance preglomerular vascular tone in juxtamedullary nephrons of young SHR, which may contribute to the resetting of the pressure-natriuretic relation.