title: Renoprotective effects of neuronal NOS-derived nitric oxide and cyclooxygenase-2 metabolites in transgenic rats with inducible malignant hypertension.
abstract: The present study was performed to determine the effects of neuronal nitric oxide synthase (nNOS) and cyclooxygenase-2 (COX-2) inhibition on blood pressure and renal hemodynamics in transgenic rats with inducible ANG II-dependent malignant hypertension [strain name: TGR(Cyp1a1Ren2)]. Male Cyp1a1-Ren2 rats (n = 7) were fed a normal diet containing indole-3-carbinol (I3C; 0.3%) for 6-9 days to induce malignant hypertension. Mean arterial pressure (MAP) and renal hemodynamics were assessed in pentobarbital sodium-anesthetized Cyp1a1-Ren2 rats before and during intravenous infusion of the nNOS inhibitor S-methyl-l-thiocitrulline (l-SMTC; 1 mg/h). In hypertensive Cyp1a1-Ren2 rats, l-SMTC increased MAP from 169 +/- 3 to 188 +/- 4 mmHg (P < 0.01), which was a smaller increase than in noninduced rats (124 +/- 9 to 149 +/- 9 mmHg, P < 0.01, n = 5). Additionally, l-SMTC decreased renal plasma flow (RPF) to a similar extent (-34 +/- 13 vs. -35 +/- 12%) in the hypertensive and normotensive rats (4.1 +/- 0.2 to 2.7 +/- 0.5 and 3.1 +/- 0.3 to 2.0 +/- 0.3 ml x min(-1) x g(-1), respectively, P < 0.01) but did not alter glomerular filtration rate (GFR) in either group. In additional experiments, administration of the COX-2 inhibitor, nimesulide (3 mg/kg i.v.), during simultaneous infusion of l-SMTC decreased MAP in both hypertensive and noninduced rats (182 +/- 2 to 170 +/- 3 mmHg and 153 +/- 3 to 140 +/- 3 mmHg, respectively, P < 0.01). Nimesulide also decreased RPF (1.9 +/- 0.2 to 0.8 +/- 0.1 ml x min(-1) x g(-1), P < 0.01) and GFR (0.9 +/- 0.1 to 0.4 +/- 0.1 ml x min(-1) x g(-1), P < 0.01) in hypertensive rats but did not alter RPF or GFR in noninduced rats. The present findings demonstrate that both nNOS-derived NO and COX-2 metabolites exert pronounced renal vasodilator influences in hypertensive Cyp1a1-Ren2 rats. The data also indicate that the renal vasodilator effects of COX-2-derived prostanoids in hypertensive Cyp1a1-Ren2 rats are not dependent on nNOS activity.
authors.affiliation: Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Patterson
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Mitchell
mesh_terms: D000804:Angiotensin II; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006974:Hypertension, Malignant / Q000139:chemically induced / Q000378:metabolism*; D007211:Indoles; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D012083:Renin / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; C473112:Ren2 protein, mouse; D013449:Sulfonamides; D000804:Angiotensin II; D002956:Citrulline; C016517:indole-3-carbinol; D052248:Nitric Oxide Synthase Type I; D019363:Cytochrome P-450 CYP1A1; D051546:Cyclooxygenase 2; D012083:Renin; D013890:Thiourea; C086717:S-methylthiocitrulline; C012655:nimesulide