Nitric oxide/cytochrome P450 interactions in cyclosporin A-induced effects in the rat.
BACKGROUND
The present study evaluated the contribution of 20-hydroxyeicosatetraenoic acid (20-HETE) and its interaction with nitric oxide (NO) in cyclosporin A-induced nephrotoxicity and hypertension.


RESULTS
The treatment of rats with cyclosporin A (25 mg/kg) for 7 days increased the renal microsomal conversion of arachidonic acid (AA) to 20-HETE (93 +/- 6%, P < 0.05), increased systolic blood pressure (SBP), reduced the urinary excretion of nitrite (53 +/- 8%, P < 0.05), induced renal damage as indicated by a marked increase in protein excretion (163 +/- 14%, P < 0.05), increased renal vasoconstrictor responses to AA (82 +/- 5%, P < 0.05) but not endothelin-1 or phenylephrine, and decreased vasodilator responses to bradykinin (42 +/- 10%, P < 0.05) and sodium nitroprusside (SNP; 56 +/- 13%, P < 0.05) in the renal preglomerular vessel treated with indomethacin and NO synthase inhibitor. The pretreatment of rats with HET0016 (10 mg/kg) or 1-aminobenzotriazole (50 mg/kg), inhibitors of cytochrome P450 (CYP450) activity, attenuated or prevented cyclosporin A-induced increases in 20-HETE production, SBP, and protein excretion, as did L-arginine (4 g/l), a substrate for NO synthase. L-Arginine but not HET0016 or 1-aminobenzotriazole blunted the cyclosporin A-induced decrease in nitrite excretion. Similarly, L-arginine blunted the enhanced vasoconstriction by AA as did HET0016 or 1-aminobenzotriazole. However, cyclosporin A-blunted dilator responses to bradykinin and SNP were not affected by L-arginine, HET0016, or 1-aminobenzotriazole.


CONCLUSIONS
These data suggest that cyclosporin A-induced nephrotoxicity can be accounted for by reduced NO production and a consequent increase in 20-HETE. The cyclosporin A-induced nephrotoxicity is thus an ideal model for evaluating NO/CYP450 interactions.
Blanton
Ahmad
A
Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA.
Nsaif
Rami
R
Hercule
Hantz
H
Oyekan
Adebayo
A
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001794:Blood Pressure; D001920:Bradykinin / Q000378:metabolism; D016572:Cyclosporine / Q000378:metabolism* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D019332:Endothelin-1 / Q000096:biosynthesis; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007668:Kidney / Q000473:pathology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000494:pharmacology
D000578:Amidines; D019332:Endothelin-1; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D014230:Triazoles; C033020:1-aminobenzotriazole; D009599:Nitroprusside; D010656:Phenylephrine; D009569:Nitric Oxide; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D001120:Arginine; D001920:Bradykinin