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: Matthew E Patterson, John J Mullins, Kenneth D Mitchell
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 294 Issue 1 Pg. F205-11 (Jan 2008) ISSN: 1931-857X [Print] United States
• PMID: 17977909 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclooxygenase Inhibitors
• Enzyme Inhibitors
• Indoles
• Ren2 protein, mouse
• Sulfonamides
• Angiotensin II
• Citrulline
• indole-3-carbinol
• Nitric Oxide Synthase Type I
• Cytochrome P-450 CYP1A1
• Cyclooxygenase 2
• Renin
• Thiourea
• S-methylthiocitrulline
• nimesulide

Topics

• Angiotensin II
• Animals
• Animals, Genetically Modified
• Blood Pressure (drug effects, physiology)
• Citrulline (analogs & derivatives, pharmacology)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase Inhibitors (pharmacology)
• Cytochrome P-450 CYP1A1 (genetics, metabolism)
• Enzyme Inhibitors (pharmacology)
• Hypertension, Malignant (chemically induced, metabolism)
• Indoles
• Kidney (blood supply, drug effects, metabolism)
• Male
• Nitric Oxide Synthase Type I (antagonists & inhibitors, metabolism)
• Rats
• Regional Blood Flow (drug effects)
• Renin (genetics, metabolism)
• Sulfonamides (pharmacology)
• Thiourea (analogs & derivatives, pharmacology)
• Vasoconstriction