Abstract
IntroductionThis 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. MethodsMale Cyplal-Ren2 rats (n=6) were fed a normal diet containing 0.15% indole-3-carbinol (I3C) for 16days 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. ResultsIn rats induced with I3C, systolic blood pressure increased by day 3 (130 ± 7–160 ± 5mm Hg, P < 0.01) and continued to increase to 191 ± 6mm Hg (P < 0.001) by day 16. In a separate group of rats (n=6), chronic administration of the direct renin inhibitor, aliskiren (30mg/kg/d, sc), prevented the development of hypertension (113 ± 5 versus 114 ± 5mm Hg, not significant). Rats treated with aliskiren exhibited significantly lower mean arterial pressure (138 ± 4 versus 201 ± 6mm Hg, P < 0.001), renal vascular resistance (23 ± 4 versus 38 ± 3mm 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 ± 0.21mL/min · g, P < 0.01) and glomerular filtration rate (1.19 ± 0.07 versus 0.78 ± 0.08mL/min · g, P< 0.01), compared with induced rats not treated chronically with aliskiren. ConclusionsThe 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.
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