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Interactive effects of superoxide anion and nitric oxide on blood pressure and renal hemodynamics in transgenic rats with inducible malignant hypertension

¹Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana; and ²Centre for Cardiovascular Science, The University of Edinburgh Medical School, Edinburgh, United Kingdom

Submitted 23 November 2004 ; accepted in final form 11 May 2005

Superoxide anion contributes to the pathogenesis of various forms of hypertension, but its role in the development of malignant hypertension remains unclear. The present study was performed to determine the influence of superoxide anion on blood pressure and renal hemodynamics in transgenic rats with inducible malignant hypertension [strain name: TGR(Cyp1a1Ren2)]. Malignant hypertension was induced in male Cyp1a1-Ren2 rats (n = 6) through dietary administration of the aryl hydrocarbon, indole-3-carbinol (0.3%) for 7–9 days. Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital sodium-anesthetized Cyp1a1-Ren2 rats before and during intravenous infusion of the superoxide dismutase mimetic tempol (100 µmol/h). Basal MAP and renal vascular resistance (RVR) were elevated in rats induced with indole-3-carbinol compared with noninduced rats (n = 5) (184 ± 4 vs. 127 ± 3 mmHg, P < 0.01, and 29 ± 2 vs. 21 ± 1 mmHg·ml^–1·min·g, P < 0.01, respectively). Hypertensive rats had elevated excretion of urinary 8-isoprostane compared with normotensive rats (41 ± 4 vs. 13 ± 6 pg·min^–1·g^–1, P < 0.01). There were no differences in renal plasma flow and glomerular filtration rate between groups. Systemic administration of tempol decreased MAP (184 ± 4 to 151 ± 4 mmHg, P < 0.01) and RVR (29 ± 2 to 25 ± 2 mmHg·ml^–1·min·g, P < 0.05) in hypertensive but not in normotensive Cyp1a1-Ren2 rats. In addition, tempol administration decreased urinary excretion of 8-isoprostane (41 ± 4 to 25 ± 4 pg·min^–1·g^–1, P < 0.05). Renal plasma flow and glomerular filtration rate remained unaltered during tempol administration in both groups. The administration of the nitric oxide synthase inhibitor nitro-L-arginine attenuated the decrease in MAP and RVR in response to tempol. These findings indicate that superoxide anion contributes to the elevated RVR and increased arterial blood pressure, by a mechanism that is at least in part nitric oxide dependent, in Cyp1a1-Ren2 rats with malignant hypertension.

tempol; kidney; renin-angiotensin system; GFR; peptide hormones

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