Renal cytochrome p450 oxygenases and preglomerular vascular response to arachidonic acid and endothelin-1 following ischemia/reperfusion.
This study tested the hypothesis that cytochrome P450 (P450) metabolites of arachidonic acid (AA) contribute to the vascular changes in ischemia/reperfusion (I/R) injury in the rat. In this study, P450-dependent omega-hydroxylase-mediated vascular reactivity of the rat renal interlobular and arcuate vessels [preglomerular vessels (PGMV)] was measured in left kidneys subjected to I/R. Clipping the left renal artery and vein for 30 min followed by reperfusion (I/R) for 3, 6, and 24 h markedly reduced renal microsomal omega-hydroxylase-mediated conversion of [(14)C]AA to 20-hydroxyeicosatetraenoic acid (HETE) that amounted to 34, 37, and 58% of the control enzyme activity, respectively. CYP4A protein expression was also reduced. There was no significant change in epoxygenase activity. Despite these changes, constriction of the rat PGMV by AA or endothelin-1 (ET-1) was not different in vessels from the clipped and nonclipped (contralateral) kidney. Clofibrate (250 mg/kg i.p.), an inducer of CYP4A protein and omega-hydroxylase enzymes, did not increase 20-HETE production but selectively enhanced the vasoconstriction produced by AA and ET-1 in the clipped but not the contralateral kidney without affecting the constriction produced by 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F(2alpha). On the other hand, administration of 2% NaCl (w/v, orally for 7 days) to induce P450-dependent epoxygenase activity attenuated AA-induced vasoconstriction but enhanced ET-1-induced vasoconstriction only in the clipped kidney. These data indicate that the reduction in CYP4A protein expression and enzyme activity in I/R is an adaptive mechanism to preserve renal vasculature from excessive vasoconstriction. Moreover, the increase in epoxygenase activity following salt loading may account for the diminished vasoconstriction evoked by AA. However, the enhancing effect of salt on ET-1-induced vasoconstriction in I/R appears to result from an overwhelming effect of salt-induced sensitization of the renal vasculature to ET-1 over the enhanced production of dilator epoxygenase products.
Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
Hantz
H
Hercule
Adebayo
A
Oyekan
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology*; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000201:enzymology*; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D023421:Models, Animal; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology*; D013997:Time Factors
D019332:Endothelin-1; D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D009251:NADPH-Ferrihemoprotein Reductase