Chronic direct renin inhibition with aliskiren prevents the development of hypertension in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent hypertension

Abstract

Introduction: This study was performed to determine whether chronic direct renin inhibition can prevent the development of slowly progressive angiotensin (ANG) II-dependent hypertension and the associated derangements in renal function in Cyplal-Ren2 transgenic rats with inducible expression of the Ren2 gene.

Methods: Male Cyplal-Ren2 rats (n = 6) were fed a normal diet containing 0.15% indole-3-carbinol (I3C) for 16 days to induce slowly progressive ANG II-dependent hypertension. Conscious systolic blood pressure was measured daily using tail-cuff plethysmography. The rats were then anesthetized with pentobarbital sodium and surgically prepared for the measurement of mean arterial pressure (MAP) and renal hemodynamics and excretory function.

Results: In rats induced with I3C, systolic blood pressure increased by day 3 (130 ± 7-160 ± 5 mm Hg, P < 0.01) and continued to increase to 191 ± 6 mm Hg (P < 0.001) by day 16. In a separate group of rats (n = 6), chronic administration of the direct renin inhibitor, aliskiren (30 mg/kg/d, sc), prevented the development of hypertension (113 ± 5 versus 114 ± 5 mm Hg, not significant). Rats treated with aliskiren exhibited significantly lower mean arterial pressure (138 ± 4 versus 201 ± 6 mm Hg, P < 0.001), renal vascular resistance (23 ± 4 versus 38 ± 3 mm Hg/mL/min · g, P < 0.01), urine flow (17.6 ± 1.4 versus 25.1 ± 2.9 μL/min, P < 0.05) and urinary sodium excretion (1.11 ± 0.32 versus 2.35 ± 0.28 μEq/min, P < 0.05) and higher renal plasma flow (4.22 ± 0.23 versus 2.56 ± 0.21 mL/min · g, P < 0.01) and glomerular filtration rate (1.19 ± 0.07 versus 0.78 ± 0.08 mL/min · g, P< 0.01), compared with induced rats not treated chronically with aliskiren.

Conclusions: The present findings demonstrate that chronic direct renin inhibition with aliskiren prevents the development of ANG II-dependent hypertension and the associated derangements in renal hemodynamics and excretory function in Cyplal-Ren2 transgenic rats.

FIG. 1

Conscious systolic blood pressures in noninduced (circle), 0.15% I3C-induced (square), and 0.15% I3C + aliskiren treated (triangle) Cyp1a1-Ren2 rats. *P<0.05 vs. day 0 within group. † P<0.05 vs. 0.15% I3C-induced rats on corresponding day.

FIG. 2

Change in body weight in noninduced (circle), 0.15% I3C-induced (square), and 0.15% I3C + aliskiren treated (triangle) Cyp1a1-Ren2 rats. *P<0.05 vs. day 0 within group. † P<0.05 vs. noninduced and 0.15% I3C-induced + aliskiren treated rats on corresponding day.

FIG. 3

Mean arterial blood pressure in noninduced (solid bars), 0.15% I3C-induced (hatched bars), and 0.15% I3C + aliskiren treated (cross hatched bars) Cyp1a1-Ren2 rats. *P<0.05 vs. noninduced. † P<0.05 vs. 0.15% I3C-induced.

FIG. 4

Glomerular filtration rate in noninduced (solid bars), 0.15% I3C-induced (hatched bars), and 0.15% I3C + aliskiren treated (cross hatched bars) Cyp1a1-Ren2 rats. *P<0.05 vs. noninduced. † P<0.05 vs. 0.15% I3C-induced.

FIG. 5

Renal plasma flow in noninduced (solid bars), 0.15% I3C-induced (hatched bars), and 0.15% I3C + aliskiren treated (cross hatched bars) Cyp1a1-Ren2 rats. *P<0.05 vs. noninduced. † P<0.05 vs. 0.15% I3C-induced.

FIG. 6

Renal vascular resistance in noninduced (solid bars), 0.15% I3C-induced (hatched bars), and 0.15% I3C + aliskiren treated (cross hatched bars) Cyp1a1-Ren2 rats. *P<0.05 vs. noninduced. † P<0.05 vs. 0.15% I3C-induced.

FIG. 7

Urine flow in noninduced (solid bars), 0.15% I3C-induced (hatched bars), and 0.15% I3C + aliskiren treated (cross hatched bars) Cyp1a1-Ren2 rats. *P<0.05 vs. noninduced. † P<0.05 vs. 0.15% I3C-induced.

FIG. 8

Urinary sodium excretion in noninduced (solid bars), 0.15% I3C-induced (hatched bars), and 0.15% I3C + aliskiren treated (cross hatched bars) Cyp1a1-Ren2 rats. *P<0.05 vs. noninduced. † P<0.05 vs. 0.15% I3C-induced.

FIG. 9

Fractional sodium excretion in noninduced (solid bars), 0.15% I3C-induced (hatched bars), and 0.15% I3C + aliskiren treated (cross hatched bars) Cyp1a1-Ren2 rats. *P<0.05 vs. noninduced. † P<0.05 vs. 0.15% I3C-induced.