Changes in renal haemodynamics induced by indomethacin in the rat involve cytochrome P450 arachidonic acid-dependent epoxygenases.
A significant renal vasodilation was observed previously after an acute cyclo-oxygenase (COX) inhibition induced with indomethacin. Because this effect could be due to COX-dependent intrarenal metabolization of arachidonic acid through cytochrome P450 (CYP450) pathways, the aim of the present study was to investigate, in vivo, possible interactions between COX and CYP450 mono-oxygenases. Mean arterial pressure (MAP) and renal blood flow (RBF), using an electromagnetic flow transducer for RBF evaluation, were measured continuously in 71 anaesthetized euvolaemic rats. Appropriate solvents (vehicle), 3 mg/kg indomethacin, 17-octadecynoic acid (17-ODYA; 2 mmol/L), either miconazole (MI; 1.5 mmol/L) or N-methylsulphonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 5 mg/kg) and N'-hydroxyphenylformamidine (HET0016; 5 or 10 mg/kg) were administered to inhibit either COX, CYP450 mono-oxygenases, epoxygenases or hydroxylase, respectively. The CYP450 and COX inhibitors were also combined as follows: 17-ODYA/indomethacin, MI (or MS-PPOH)/indomethacin, HET0016/indomethacin and indomethacin/HET0016. Mean arterial pressure and RBF were not modified by vehicle, 17-ODYA or MI (or MS-PPOH). However, MAP decreased slightly (P < 0.05; paired t-test, 5 d.f.) and RBF increased transiently (P < 0.05; anova, 5 d.f.) after HET0016. In contrast, MAP decreased by 10 mmHg (P < 0.05) and RBF increased by 10% (P < 0.05) after indomethacin. This enhancement was prevented by 17-ODYA or MI (or MS-PPOH), but not by HET0016. Moreover, RBF increased step-wise to 21% in the indomethacin/HET0016 experiment (P < 0.05). Consequently, changes from baseline in renal vascular resistance differed among treatments, averaging -2 +/- 3 (vehicle), -13 +/- 3 (indomethacin; P < 0.05 vs vehicle), -4 +/- 3 (17-ODYA/indomethacin), -3 +/- 4 (MI or MS-PPOH/indomethacin), -15 +/- 3 (HET0016/indomethacin; P < 0.05) and -22 +/- 4% (indomethacin/HET0016; P < 0.05). In conclusion, these results demonstrate that the renal vasodilation induced by indomethacin can be prevented by prior inhibition of CYP450 mono-oxygenases and further suggest that the CYP450 epoxygenases pathway may prevail.
Caron
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N
Service de Physiologie et de Pharmacologie, Faculté de Médecine, Université de Mons-Hainaut, Mons, Belgium.
El Hajjam
A
A
Declèves
A-E
AE
Joly
E
E
Falck
J R
JR
Kramp
R
R
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008297:Male; D008825:Miconazole / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; C047008:17-octadecynoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D007213:Indomethacin