thiourea and nimesulide

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.

Topics: Angiotensin II; Animals; Animals, Genetically Modified; Blood Pressure; Citrulline; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Cytochrome P-450 CYP1A1; Enzyme Inhibitors; Hypertension, Malignant; Indoles; Kidney; Male; Nitric Oxide Synthase Type I; Rats; Regional Blood Flow; Renin; Sulfonamides; Thiourea; Vasoconstriction

Burn injury has been shown to impair intestinal transit. p38 mitogen-activated protein kinase (MAPK) has been shown to be involved in the production of proinflammatory mediators such as interleukin (IL)-1beta, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). The aims of this study were to investigate the effects of SB203580, a specific p38 MAPK inhibitor, on intestinal transit and to elucidate its possible mechanism.. Burn rats and sham rats were divided into 4 groups: saline, S-methylisothiourea (a selective iNOS inhibitor), nimesulide (a selective COX-2 inhibitor), or SB203580. Intestinal transit was measured using phenol red and assessed using the geometric center. The protein or gene expression of NOS, COX-2, and IL-1beta were measured by real-time reverse-transcription polymerase chain reaction or Western blot analysis. p38 MAPK activity or myeloperoxidase (MPO) activity was determined by using the p38 MAPK assay kit or MPO assay kit.. Intestinal transit was delayed significantly with burn injury, improved significantly with S-methylisothiourea and nimesulide, but almost completely normalized with SB203580. p38 MAPK activity, MPO activity, iNOS, COX-2, and IL-1beta protein or gene expression increased markedly after burn injury. SB203580 inhibited p38 MAPK and MPO activity, and reduced iNOS, COX-2, and IL-1beta protein or gene expression.. Burn-induced delayed intestinal transit is associated with the p38 MAPK pathway. Inhibition of the p38 MAPK pathway ameliorates delayed intestinal transit, at least in part, by inhibiting iNOS, COX-2, and IL-1beta expression. Thus, p38 MAPK could represent a novel target for therapy of gut dysmotility after burn injury.

Topics: Animals; Burns; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Enzyme Inhibitors; Gastrointestinal Transit; Imidazoles; Intestinal Diseases; Male; p38 Mitogen-Activated Protein Kinases; Pyridines; Rats; Rats, Sprague-Dawley; Sulfonamides; Thiourea