scholarly journals Chronic direct renin inhibition with aliskiren normalizes blood pressure and improves renal hemodynamics in Cyp1a1‐Ren2 transgenic rats with ANG II‐dependent malignant hypertension

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Catherine G Howard ◽  
Kenneth D Mitchell
Keyword(s):  
Blood Pressure ◽  
Renal Hemodynamics ◽  
Malignant Hypertension ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Renin Inhibition

scholarly journals Renal functional responses to selective intrarenal renin inhibition in Cyp1a1-Ren2 transgenic rats with ANG II-dependent malignant hypertension

2012 ◽  
Vol 302 (1) ◽  
pp. F52-F59 ◽  
Author(s):  
Catherine G. Howard ◽  
Kenneth D. Mitchell
Keyword(s):  
De Novo ◽  
Collecting Duct ◽  
Renal Plasma Flow ◽  
Renin Angiotensin System ◽  
Malignant Hypertension ◽  
Ang Ii ◽  
Functional Responses ◽  
Transgenic Rats ◽  
Excretory Function ◽  
Renin Inhibition

Angiotensin (ANG) II-dependent hypertension is characterized by increases in intrarenal ANG II levels, derangement in renal hemodynamics, and augmented tubular sodium reabsorptive capability. Increased nephron expression of renin-angiotensin system components, such as angiotensinogen by proximal tubule cells and renin by collecting duct principal cells, has been associated with an augmented ability of the kidney to form ANG II in hypertensive states. However, the contribution of de novo intrarenal ANG II production to the development and maintenance of ANG II-dependent hypertension remains unclear. The present study was performed to determine the effects of selective intrarenal renin inhibition on whole kidney hemodynamics and renal excretory function in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension in the absence of the confounding influence of associated reductions in mean arterial pressure (MAP). Male Cyp1a1-Ren2 transgenic rats were induced to develop malignant hypertension, anesthetized, and surgically prepared for intrarenal administration of the direct renin inhibitor aliskiren (0.01 mg/kg). Following acute aliskiren treatment, urine flow and sodium excretion increased (10.5 ± 1.1 to 15.9 ± 1.9 μl/min, P < 0.001; 550 ± 160 to 1,370 ± 320 neq/min, P < 0.001, respectively) and ANG II excretion decreased (120 ± 30 to 63 ± 17 fmol/h, P < 0.05). There were no significant changes in MAP, glomerular filtration rate, estimated renal plasma flow, plasma ANG II levels, or protein excretion. The present findings demonstrate that selective renal renin inhibition elicits diuretic and natriuretic responses in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. Elevated intraluminal ANG II levels likely act to augment tubular reabsorptive function and, thereby, contribute to the elevated blood pressure in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension.

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

2005 ◽  
Vol 289 (4) ◽  
pp. F754-F759 ◽  
Author(s):  
Matthew E. Patterson ◽  
Cynthia R. Mouton ◽  
John J. Mullins ◽  
Kenneth D. Mitchell
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Glomerular Filtration Rate ◽  
Plasma Flow ◽  
Superoxide Anion ◽  
Filtration Rate ◽  
Renal Plasma Flow ◽  
Renal Hemodynamics ◽  
Malignant Hypertension ◽  
Transgenic Rats

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.

Cyclooxygenase-2 inhibition normalizes arterial blood pressure in CYP1A1-REN2 transgenic rats with inducible ANG II-dependent malignant hypertension

2006 ◽  
Vol 291 (3) ◽  
pp. F612-F618 ◽  
Author(s):  
Allison L. Opay ◽  
Cynthia R. Mouton ◽  
John J. Mullins ◽  
Kenneth D. Mitchell
Keyword(s):  
Blood Pressure ◽  
Renal Plasma Flow ◽  
Renal Hemodynamics ◽  
Malignant Hypertension ◽  
Hypertensive Rats ◽  
Transgenic Rats ◽  
Arterial Blood ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Cox 1

The present study was performed to determine the effects of cyclooxygenase (COX)-1 and COX-2 inhibition on blood pressure and renal hemodynamics in transgenic rats with inducible malignant hypertension [strain name: TGR(Cyp1a1Ren2)]. Male Cyp1a1-Ren2 rats ( n = 7) were fed a normal diet containing the aryl hydrocarbon, indole-3-carbinol (I3C; 0.3%), for 6–9 days to induce malignant hypertension. Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital sodium-anesthetized Cyp1a1-Ren2 rats during control conditions, following administration of the COX-2 inhibitor nimesulide (3 mg/kg iv), and following administration of the nonspecific COX inhibitor meclofenamate (5 mg/kg iv). Rats induced with I3C had higher MAP than noninduced rats ( n = 7; 188 ± 6 vs. 136 ± 4 mmHg, P < 0.01). There was no difference in renal plasma flow (RPF) or glomerular filtration rate (GFR) between induced and noninduced rats. Nimesulide elicited a larger decrease in MAP in hypertensive rats (188 ± 6 to 140 ± 8 mmHg, P < 0.01) than in normotensive rats (136 ± 4 to 113 ± 8 mmHg, P < 0.01). Additionally, nimesulide decreased GFR (0.9 ± 0.13 to 0.44 ± 0.05 ml·min−1·g−1, P < 0.05) and RPF (2.79 ± 0.27 to 1.35 ± 0.14 ml·min−1·g−1, P < 0.05) in hypertensive rats but did not alter GFR or RPF in normotensive rats. Meclofenamate further decreased MAP in hypertensive rats (to 115 ± 10 mmHg, P < 0.05) but did not decrease MAP in normotensive rats. Meclofenamate did not alter GFR or RPF in either group. These findings demonstrate that COX-1- and COX-2-derived prostanoids contribute importantly to the development of malignant hypertension in Cyp1a1-Ren2 transgenic rats. The data also indicate that COX-2-derived vasodilatory metabolites play an important role in the maintenance of RPF and GFR following induction of malignant hypertension in Cyp1a1-Ren2 transgenic rats.

scholarly journals 20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Lenka Sedláková ◽  
Soňa Kikerlová ◽  
Zuzana Husková ◽  
Lenka Červenková ◽  
Věra Čertíková Chábová ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cytochrome P450 ◽  
Cardiac Injury ◽  
Malignant Hypertension ◽  
Ang Ii ◽  
Hydroxyeicosatetraenoic Acid ◽  
Hypertensive Rats ◽  
Transgenic Rats ◽  
Renin Gene ◽  
Marked Suppression

We hypothesized that vascular actions of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of cytochrome P450 (CYP450)-dependent ω-hydroxylase, potentiate prohypertensive actions of angiotensin II (ANG II) in Cyp1a1-Ren-2 transgenic rats, a model of ANG II-dependent malignant hypertension. Therefore, we evaluated the antihypertensive effectiveness of 20-HETE receptor antagonist (AAA) in this model. Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. Treatment with AAA was started either simultaneously with induction of hypertension or 10 days later, during established hypertension. Systolic blood pressure (SBP) was monitored by radiotelemetry, indices of renal and cardiac injury, and kidney ANG II levels were determined. In I3C-induced hypertensive rats, early AAA treatment reduced SBP elevation (to 161 ± 3 compared with 199 ± 3 mmHg in untreated I3C-induced rats), reduced albuminuria, glomerulosclerosis index, and cardiac hypertrophy (P<0.05 in all cases). Untreated I3C-induced rats showed augmented kidney ANG II (405 ± 14 compared with 52 ± 3 fmol/g in non-induced rats, P<0.05) which was markedly lowered by AAA treatment (72 ± 6 fmol/g). Remarkably, in TGR with established hypertension, AAA also decreased SBP (from 187 ± 4 to 158 ± 4 mmHg, P<0.05) and exhibited organoprotective effects in addition to marked suppression of kidney ANG II levels. In conclusion, 20-HETE antagonist attenuated the development and largely reversed the established ANG II-dependent malignant hypertension, likely via suppression of intrarenal ANG II levels. This suggests that intrarenal ANG II activation by 20-HETE is important in the pathophysiology of this hypertension form.

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