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

Abstract

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 mumol/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.

Genetic Clamping of Renin Gene Expression Induces Hypertension and Elevation of Intrarenal Ang II Levels of Graded Severity in Cyp1a1-Ren2 Transgenic Rats

“…Thus, the severe phenotype induced by the high dose of I3C is characteristic of malignant hypertension. 9,23,[31][32][33][34] Dietary administration of high-dose I3C did not alter either systolic blood pressure (144±5 vs. 147±6 mmHg) or body weight 307±10 vs. 322±6 g) of transgene-negative rats, indicating that the I3C-induced hypertension and weight loss were not the result of non-specific effects of I3C. Indeed, chronic administration of the AT 1 -receptor antagonist, candesartan, prevented the development of hypertension and loss of body weight in Cyp1a1-Ren2 transgenic rats induced with high-dose I3C.…”

“…22 To induce malignant hypertension, group 3 rats (n=7) were fed a higher dose of I3C (0.3%, w/w; diet TD 00554, Harlan-Teklad) as described previously. 23 For this group, we had initially planned to induce with high-dose I3C for 14-15 days (i.e. for a duration comparable to the low-dose induction group); however, the rats induced with the higher dose of I3C exhibited severe loss of body weight, extreme lethargy, piloerection, and assumption of hunched posture which necessitated early termination of dietary I3C treatment.…”

“…[18][19][20][21]24 In contrast, at a higher dose of 0.3% (w/w), dietary I3C induces malignant hypertension characterised by severe loss of body weight, lethargy and piloerection. 23 Although Ang II-mediated alterations in renal haemodynamics and tubular reabsorption contribute importantly to both hypertensive phenotypes, there is uncertainty regarding the prevailing levels of the components of the RAS following induction of either slowly developing or malignant hypertension in Cyp1a1-Ren2 transgenic rats. In this regard, Kantachuvesiri et al 9 initially reported that all components of the circulating RAS were increased in Cyp1a1-Ren2 rats induced with 0.3% I3C for seven days.…”

Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

“…Accordingly, this model allows induction of ANG II-dependent hypertension of graded severity using a benign and naturally occurring dietary supplement without the need for surgical intervention, dietary salt manipulation, or the administration of steroids (23,27). In essence, the Cyp1a1-Ren2 transgenic rat model is particularly advantageous because of the ease and reproducibility of genetically clamping expression of the Ren2 gene and inducing increases in plasma renin activity, plasma and intrarenal ANG II levels, and hypertension of graded severity (22,27,28,31,32).We have demonstrated that at a dose of 0.3% (wt/wt), chronic dietary administration of I3C induces malignant hypertension in Cyp1a1-Ren2 transgenic rats (27,28,31,32). Malignant hypertension is a severe form of hypertension characterized by rapidly increasing blood pressure, pressure diuresis and natriuresis, severe renal vasoconstriction and ischemia, activation of the renin-angiotensin system, microangiopathy, hemolytic anemia, and development of retinopathy (23,47,48).…”

“…Accordingly, this model allows induction of ANG II-dependent hypertension of graded severity using a benign and naturally occurring dietary supplement without the need for surgical intervention, dietary salt manipulation, or the administration of steroids (23,27). In essence, the Cyp1a1-Ren2 transgenic rat model is particularly advantageous because of the ease and reproducibility of genetically clamping expression of the Ren2 gene and inducing increases in plasma renin activity, plasma and intrarenal ANG II levels, and hypertension of graded severity (22,27,28,31,32).…”