Blockade of cytochrome P-450 epoxygenase pathway attenuates the natriuresis of N(G)-monomethyl-L-arginine infusion in the spontaneously hypertensive rat

Ali A. Khraibi, Keith H. Taylor, Carla R. Ramsey, Theresa J. Berndt

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Abstract

Previous studies demonstrated that there is increased renal synthesis of cytochrome P-450-dependent arachidonic acid metabolites in the vasculature and tubules of the Okamoto spontaneously hypertensive rat (SHR). It has also been shown that the natriuretic response of the SHR to N(G)-monomethyl-L-arginine (L-NMMA) infusion is exaggerated compared with that of the normotensive Wistar-Kyoto rat. The purpose of this study was to determine the roles of cytochrome P-450 epoxygenase and cyclooxygenase pathways in the natriuresis that is observed with the systemic infusion of a high dose of L-NMMA to inhibit nitric oxide synthesis in the SHR and the Wistar-Kyoto rats. After a control clearance period of 20 minutes groups of adult SHR (n = 14) were given L-NMMA (15 mg/kg bolus followed by 500 μg/kg/min continuous infusion). In other groups of SHR either ketoconazole (0.5 mg/kg, n = 9) to inhibit the renal activity of cytochrome P-450 epoxygenase pathway or indomethacin (3 mg/kg, n = 7) to inhibit cyclooxygenase activity was administered intravenously 20 minutes before the control clearance period. After the control clearance period L-NMMA was infused as previously described. Infusion of L-NMMA in the control group of SHR resulted in a significant increase in fractional excretion of sodium (FE(Na) from 1.78% ± 0.24% ± 6.90% ± 0.61%). In the ketoconazole-treated group of SHR, L-NMMA infusion resulted in a significant natriuresis (from 2.22% ± 0.58% to 4.70% ± 0.93%); however, the natriuretic response was significantly attenuated compared with that of the control group of SHR that received only L-NMMA (ΔFE(Na), 2.47% ± 0.40% vs 5.24% ± 0.55%). Indomethacin administration did not affect the natriuretic response to L-NMMA infusion in the SHR. In conclusion, the natriuretic response to L-NMMA infusion in the SHR is significantly attenuated by administration at ketoconazole but not indomethacin. This result suggests that the natriuretic effect of L-NMMA infusion in the SHR is mediated at least partly by cytochrome P-450 metabolites of the epoxygenase pathway.

Original languageBritish English
Pages (from-to)330-336
Number of pages7
JournalJournal of Laboratory and Clinical Medicine
Volume129
Issue number3
DOIs
StatePublished - Mar 1997

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