Role of cytochrome P-450 in elevating renal vascular tone in spontaneously hypertensive rats.
The contribution of cytochrome P-450 metabolites of arachidonic acid in elevating vascular tone in the kidneys of adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was examined using a juxtamedullary nephron microvascular preparation perfused in vitro with a physiological salt solution containing 5% albumin. At 80 mm Hg, the basal internal diameters of arcuate and interlobular arteries and proximal and distal afferent arterioles of the SHR averaged 341 +/- 15.81 +/- 5.24 +/- 0.5 and 19 +/- 0.3 micron, respectively. These diameters were 5-29% smaller (p < 0.05) than those measured in corresponding vessels in WKY rats. Addition of the P-450 inhibitors, ketoconazole (100 microM) or 17-octadecynoic acid (17-ODYA, 20 microM), to the perfusate and bath increased the diameters of the preglomerular vasculature of the SHR by 6-29%, but by only 3-13% in WKY rats and reduced significantly the differences in pressure-diameter relations between the two groups. The rate of formation of 20-hydroxyeicosatetraenoic acid (20-HETE) by renal cortical microsomes was similar in SHR and WKY rats. However, the production of epoxyeicosatrienoic acids (EETs) by cortical microsomes was 87% lower and dihydroxyeicosatrienoic acids (DHETs) 70% higher in the SHR than WKY rats. Ketoconazole (100 microM) reduced the formation of 20-HETE by 80%, and EETs and DHETs production by more than 98% in SHR and WKY rats. 17-ODYA (20 microM) reduced the formation of 20-HETE, EETs and DHETs by more than 98% in both groups. These results suggest that cytochrome P-450 metabolites of arachidonic acid contribute to the elevated renal vascular tone in adult SHR. This may be due to an enhanced vascular responsiveness to vasoconstrictor P-450 metabolites in SHR or an elevated local production of vasoconstrictor eicosanoids in the renal vasculature of SHR rather than in renal cortical tissue.
Gebremedhin
D
D
Department of Physiology, Medical College of Wisconsin, Milwaukee 53226.
Ma
Y H
YH
Imig
J D
JD
Harder
D R
DR
Roman
R J
RJ
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D015777:Eicosanoids / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007654:Ketoconazole / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008833:Microcirculation / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D065607:Cytochrome P-450 Enzyme Inhibitors; D015777:Eicosanoids; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; C047008:17-octadecynoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole