title: Contribution of cytochrome P450 epoxygenase and hydroxylase pathways to afferent arteriolar autoregulatory responsiveness.
abstract: Previous studies have demonstrated an important role for the cytochrome P450 (CYT-P450) pathway in afferent arteriole autoregulatory responses but the involvement of specific pathways remains unknown. Experiments were performed to determine the role of CYT-P450 epoxygenase and hydroxylase pathways in pressure mediated preglomerular autoregulatory responses. Afferent arteriolar diameter was measured as renal perfusion pressure was increased from 80-160 mmHg. Afferent arteriolar diameter averaged 19+/-2 microm at a renal perfusion pressure of 80 mmHg and decreased by 15+/-2% when pressure was increased to 160 mmHg. Inhibition of the epoxygenase pathway with 6-(2-proparglyloxyphenyl)hexanoic acid (PPOH), enhanced the microvascular response to increasing renal perfusion pressure. In the presence of 50 microM PPOH, afferent arteriolar diameter decreased by 29+/-4% when pressure was increased from 80-160 mmHg. Likewise, the sulphonimide derivative of PPOH, N-methylsulphonyl-6-(2-proparglyloxyphenyl) hexanamide (MS-PPOH, 50 microM), enhanced the afferent arteriolar response to increasing renal perfusion pressure. In contrast, the selective CYT-P450 hydroxylase inhibitor, N-methylsulphonyl-12,12-dibromododec-11-enamide (DDMS) attenuated the vascular response to increasing renal perfusion pressure. In the pressure of 25 microM DDMS, afferent arteriolar diameter decreased by 4+/-2% when pressure was increased from 80-160 mmHg. These results suggest that CYT-P450 metabolites of the epoxygenase pathway alter afferent arteriolar responsiveness and thereby modify the ability of the preglomerular vasculature to autoregulate renal blood flow. Additionally, these results provide further support to the concept that a metabolite of the hydroxylase pathway is an integral component of the afferent arteriolar response to elevations in perfusion pressure.
authors.affiliation: Department of Physiology, SL39 Tulane University School of Medicine, New Orleans, Louisiana 70112, USA. jdimig@mailhost.tcs.tulane.edu
authors.forename: J D
authors.initials: JD
authors.lastname: Imig
authors.forename: J R
authors.initials: JR
authors.lastname: Falck
authors.forename: E W
authors.initials: EW
authors.lastname: Inscho
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology*; D002208:Caproates / Q000494:pharmacology*; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis; D007668:Kidney / Q000098:blood supply; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010477:Perfusion; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology
chemical_list: C121755:6-(2-propargyloxyphenyl)hexanoic acid; D000577:Amides; D002208:Caproates; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D013450:Sulfones; D003577:Cytochrome P-450 Enzyme System; C117975:DDMS; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2