title: Role of cytochrome P-450 arachidonate metabolites in endothelin signaling in rat proximal tubule.
abstract: We examined the rat proximal tubule (PT) response to endothelin-1 (ET-1) in terms of 20-hydroxyeicosatetraenoic acid (HETE) dependency. Arachidonic acid (AA) (1 microM) decreased ouabain-sensitive (86)Rb uptake from 2.1 +/- 0.1 to 0.3 +/- 0.08 ng Rb. 10 microg protein(-1). 2 min(-1) (P < 0.05); 20-HETE (1 microM) had similar effects. Dibromododecenoic acid (DBDD) (2 microM), an inhibitor of omega-hydroxylase, abolished the inhibitory action of AA on (86)Rb uptake whereas the PT response to 20-HETE was unaffected. ET-1 at 0.1, 1, 10, and 100 nM reduced (86)Rb uptake from 2.8 +/- 0.3 in control PTs to 2.4 +/- 0.2, 1.7 +/- 0.1, 0.67 +/- 0.08, and 0.1 +/- 0.03 ng Rb. 10 microg protein(-1). 2 min(-1), respectively. DBDD (2 microM) abolished the inhibitory effect of ET-1 on (86)Rb uptake as did BMS182874 (1 microM), an ET(A)-selective receptor antagonist. ET-1 (100 nM) significantly increased PT 20-HETE release by approximately 50%, an effect prevented by DBDD. N(omega)-nitro-L-arginine-methyl ester (L-NAME), given for 4 days to inhibit nitric oxide synthase (NOS), increased arterial pressure from 92 +/- 12 to 140 +/- 8 mmHg and increased endogenous release of 20-HETE from isolated PTs (measured by gas chromatography/mass spectrometry). In L-NAME-treated PTs, but not in control PTs, 0.1 microM AA inhibited ouabain-sensitive (86)Rb uptake by > 40%; the response to AA was attenuated by DBDD. We conclude that, in the PTs, 1) 20-HETE is a second messenger for ET-1 and 2) conversion of AA to 20-HETE is augmented when NOS is inhibited.
authors.affiliation: Centro de Investigación y de Estudios Avanzados del Institúto Politécnico Nacional, Mexico.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Escalante
authors.forename: John C
authors.initials: JC
authors.lastname: McGiff
authors.forename: Adebayo O
authors.initials: AO
authors.lastname: Oyekan
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D012414:Rubidium Radioisotopes / Q000493:pharmacokinetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D012414:Rubidium Radioisotopes; D016718:Arachidonic Acid; D009569:Nitric Oxide; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D019331:NG-Nitroarginine Methyl Ester