Blockade of cytochrome P-450 epoxygenase pathway attenuates the natriuresis of NG-monomethyl-l-arginine infusion in the spontaneously hypertensive rat
| Autor: | Theresa J. Berndt, Carla R. Ramsey, A. A. Khraibi, Keith H. Taylor |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Male
Epoxygenase medicine.medical_specialty Antifungal Agents Fractional excretion of sodium Arginine Indomethacin Nitric Oxide Cytochrome P-450 CYP2J2 Rats Inbred WKY Pathology and Forensic Medicine Natriuresis Nitric oxide chemistry.chemical_compound Spontaneously hypertensive rat Bolus (medicine) Cytochrome P-450 Enzyme System Rats Inbred SHR Internal medicine medicine Animals Cytochrome P-450 Enzyme Inhibitors Cyclooxygenase Inhibitors cardiovascular diseases omega-N-Methylarginine Dose-Response Relationship Drug biology Chemistry Sodium Age Factors Nephrons General Medicine musculoskeletal system Diuresis Rats Ketoconazole Endocrinology Prostaglandin-Endoperoxide Synthases Oxygenases cardiovascular system biology.protein Cyclooxygenase circulatory and respiratory physiology |
| Zdroj: | Journal of Laboratory and Clinical Medicine. 129:330-336 |
| ISSN: | 0022-2143 |
| DOI: | 10.1016/s0022-2143(97)90181-5 |
| Popis: | 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 NG-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 microg/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% to 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 (delta FE 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 of 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. |
| Databáze: | OpenAIRE |
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