Modulation of V1-receptor-mediated renal vasoconstriction by epoxyeicosatrienoic acids.
This study examined the effects of renal arterial infusion of a selective cytochrome P-450 epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 2 mg/kg plus 1.5 mg.kg(-1).h(-1)), on renal hemodynamic responses to infusions of [Phe(2),Ile(3),Orn(8)]vasopressin and ANG II into the renal artery of anesthetized rabbits. MS-PPOH did not affect basal renal blood flow (RBF) or cortical or medullary blood flow measured by laser-Doppler flowmetry (CLDF/MLDF). In vehicle-treated rabbits, [Phe(2),Ile(3),Orn(8)]vasopressin (30 ng.kg(-1).min(-1)) reduced MLDF by 62 +/- 7% but CLDF and RBF were unaltered. In MS-PPOH-treated rabbits, RBF and CLDF fell by 51 +/- 8 and 59 +/- 13%, respectively, when [Phe(2),Ile(3),Orn(8)]vasopressin was infused. MS-PPOH had no significant effects on the MLDF response to [Phe(2),Ile(3),Orn(8)]vasopressin (43 +/- 9% reduction). ANG II (20 ng.kg(-1).min(-1)) reduced RBF by 45 +/- 10% and CLDF by 41 +/- 14%, but MLDF was not significantly altered. MS-PPOH did not affect blood flow responses to ANG II. Formation of epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DiHETEs) was 49% lower in homogenates prepared from the renal cortex of MS-PPOH-treated rabbits than from vehicle-treated rabbits. MS-PPOH had no effect on the renal formation of 20-hydroxyeicosatetraenoic acid (20-HETE). Incubation of renal cortical homogenates from untreated rabbits with [Phe(2),Ile(3),Orn(8)]vasopressin (0.2-20 ng/ml) did not affect formation of EETs, DiHETEs, or 20-HETE. These results do not support a role for de novo EET synthesis in modulating renal hemodynamic responses to ANG II. However, EETs appear to selectively oppose V(1)-receptor-mediated vasoconstriction in the renal cortex but not in the medullary circulation and contribute to the relative insensitivity of cortical blood flow to V(1)-receptor activation [corrected].
Dept. of Physiology, P.O. Box 13F, Monash Univ., Melbourne, Victoria 3800, Australia. niwanthi.rajapakse@med.monash.edu.au
Niwanthi W
NW
Rajapakse
Richard J
RJ
Roman
John R
JR
Falck
Jeremy J
JJ
Oliver
Roger G
RG
Evans
D000577:Amides / Q000494:pharmacology; D000758:Anesthesia; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015777:Eicosanoids / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000098:blood supply / Q000187:drug effects; D007679:Kidney Medulla / Q000098:blood supply / Q000187:drug effects; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009951:Ornipressin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011817:Rabbits; D017483:Receptors, Vasopressin / Q000187:drug effects*; D012077:Renal Artery / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000577:Amides; D065607:Cytochrome P-450 Enzyme Inhibitors; D015777:Eicosanoids; D004791:Enzyme Inhibitors; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D017483:Receptors, Vasopressin; D014662:Vasoconstrictor Agents; C082351:vasopressin, Phe(2)-Ile(3)-Orn(8)-; D000804:Angiotensin II; D009951:Ornipressin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; C026961:prostaglandin omega hydroxylases