Cytochrome P450 omega/omega-1 hydroxylase-derived eicosanoids contribute to endothelin(A) and endothelin(B) receptor-mediated vasoconstriction to endothelin-1 in the rat preglomerular arteriole.
The preglomerular arteriole of the rat was used to evaluate the contribution of cytochrome P450-derived eicosanoids to the vasoconstrictor effect of endothelin (ET)-1 and to determine the receptors mediating the response. ET-1 (4 x 10(-11) to 2 x 10(-9) M) produced dose-dependent reductions in the intraluminal diameter of the renal arteriole ranging from 25 +/- 8 to 142 +/- 16 micrometer. BMS182874 [(5-dimethylamino)-N-(3, 4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; 3 microM], an ET(A) receptor antagonist, or BQ788 (N-cis-2, 6-dimethyl-piperidino-carbonyl-L-gamma-methylleucyl-D-1-methoxy carbonyl-tryptophanyl-D-norleucine; 1 microM), an ET(B) receptor antagonist, attenuated ET-1 vasoconstriction by 59 +/- 4 and 50 +/- 10%, respectively. The combined administration of both ET receptor antagonists increased inhibition of ET-1 vasoconstriction to 75 +/- 4%. 17-Octadecynoic acid (17-ODYA, 2 microM) or 12, 12-dibromododec-enoic acid (2 microM), inhibitors of 20-hydroxyeicosatetraenoic acid (20-HETE) production, attenuated ET-1-induced vasoconstriction by 50 +/- 6 and 40 +/- 3%, respectively, as did indomethacin (10 microM), an inhibitor of cyclooxygenase. Miconazole (2 microM), the epoxygenase inhibitor, was without effect. 20-HETE (10(-8) and 2 x 10(-8) M) elicited a dose-related vasoconstriction that was inhibited by 10 microM, but not 5 microM, indomethacin. The inhibition by 17-ODYA of ET-1 vasoconstriction was not greater when combined with BMS182874 or BQ788. Moreover, vasoconstriction induced by ET-3, an ET(B)-selective agonist, was inhibited by 17-ODYA. These data indicate that both ET(A) and ET(B) receptors mediate ET-1 vasoconstriction and that 20-HETE production linked to both receptors makes a major contribution to ET-1-induced renal arteriolar vasoconstriction in the rat.
Hercule
H C
HC
Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Oyekan
A O
AO
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D003619:Dansyl Compounds / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000502:physiology*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D006899:Mixed Function Oxygenases / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*
D003619:Dansyl Compounds; D019332:Endothelin-1; D006893:Hydroxyeicosatetraenoic Acids; D009842:Oligopeptides; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D015117:5,8,11,14-Eicosatetraynoic Acid; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; D016718:Arachidonic Acid; C086539:BQ 788; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D011451:Prostaglandin-Endoperoxide Synthases