aliskiren and Hypertension--Malignant

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.

Topics: Amides; Animals; Blood Pressure; Cytochrome P-450 CYP1A1; Fumarates; Hypertension, Malignant; Kidney; Male; Rats; Rats, Transgenic; Renin; Sodium

Cyp1a1-Ren2 transgenic rats [strain name: TGR(Cyp1a1Ren2)], administered indole-3-carbinol (I3C) develop angiotensin (ANG) II-dependent hypertension due to hepatic expression of the Ren2 renin gene. Although AT1 receptor blockade prevents the development of hypertension and normalizes the elevated arterial blood pressure of Cyp1-Ren2 rats, little information is available regarding the blood pressure and renal functional responses to direct inhibition of renin in this high circulating renin model of ANG II-dependent hypertension. This study was performed to determine the effects of acute direct renin inhibition with aliskiren on blood pressure and renal hemodynamics in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension.. Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital-anesthetized male Cyp1a1-Ren2 rats during control conditions and after administration of the renin inhibitor, aliskiren (10 mg/kg, intravenous).. Rats induced with I3C had higher MAP (194 ± 7 versus 141 ± 2 mm Hg, P < 0.001), lower renal plasma flow (RPF; 2.47 ± 0.23 versus 4.17 ± 0.35 mL/min/g, P < 0.001) and lower glomerular filtration rate (GFR; 1.01 ± 0.07 versus 1.34 ± 0.06 mL/min/g, P = 0.01) than noninduced Cyp1a1-Ren2 rats (n = 5). Aliskiren administration decreased MAP (194 ± 7 to 136 ± 2 mm Hg, P < 0.001) and increased RPF (2.47 ± 0.23 versus 4.31 ± 0.20 mL/min/g, P < 0.001) in hypertensive but not in normotensive rats, without altering GFR.. Acute renin inhibition with aliskiren normalizes MAP and RPF in Cyp1a1-Ren2 rats with malignant hypertension. The normalization of MAP and RPF after acute renin inhibition indicates that renin generated by expression of the Ren2 gene is responsible for the maintenance of malignant hypertension and the associated reduction in renal hemodynamic function in Cyp1a1-Ren2 rats.

Topics: Amides; Angiotensin II; Animals; Blood Pressure; Cytochrome P-450 CYP1A1; Disease Models, Animal; Fumarates; Glomerular Filtration Rate; Hypertension, Malignant; Kidney; Male; Rats; Rats, Transgenic; Regional Blood Flow; Renin; Vascular Resistance