The Direct Renin Inhibitor Aliskiren Improves Vascular Remodeling in Transgenic Rats Harboring Human Renin and Angiotensinogen Genes

Objective: The selective human renin inhibitor aliskiren (ALK) reduces blood pressure and ameliorates cardio-renal organ damage in hypertensive double transgenic rats (dTGRs) which express both human renin and angiotensinogen. Little is known about the effect of ALK on hypertension-related functional and structural alterations of resistance arteries. We tested the hypothesis that chronic treatment with ALK in dTGRs improves resistance arteries’ vascular remodeling which represents the earliest manifestation of target organ damage in hypertensive subjects and has prognostic significance. Design and method: dTGRs (5 weeks old) were treated with ALK (3 mg/kg/day, n=5) or ramipril (RAM, 1 mg/kg/day, n=5) for 14 days and compared with age-matched untreated dTGRs. Blood pressure (BP) was measured by tail-cuff method. Resistance arteries media-to-lumen ratio (M/L) was evaluated on mesenteric arteries as pressurized preparations. Endothelium-dependent and -independent relaxations were assessed by dose-responses curves to acetylcholine (Ach, 10-9 to 10-4 mol/L) and sodium nitroprusside (SNP, 10-8 to 10-4 mol/L), respectively, in vessels precontracted with norepinephrine (10-6 mol/L). The expression of AT1 receptor, AT2 receptor, eNOS and the NADPH subunit gp91phox in aorta was evaluated by immunoblotting. The reactive oxygen species (ROS) production was evaluated in aorta by Dihydroethidium (DHE) staining. Results and conclusions: BP was similarly reduced in both ALK-treated and RAM-treated rats compared to untreated dTGRs (167±1.18 mmHg and 169.4±1.5 mmHg vs 196.8 ±3.9 mmHg, respectively P<0.05; reduction of -15% and -14%; P<0.05). M/L was equally reduced in ALK-treated and RAM-treated rats compared to untreated rats (6.3±0.5 % and 6.4±0.2 % vs 9.8±.04%, respectively; P<0.05). Endothelium-dependent and –independent relaxations were not different between ALK-treated and RAM-treated dTGRs. AT1 and AT2 receptor expression was similar in all the groups. eNOS expression was increased only in ALK-treated rats (+41.3±6.3 % vs untreated dTGRs, p<0.05). gp91phox was slightly reduced in both ALK-and RAM-treated dTGRs. Both ALK and RAM similarly reduced ROS production in dTGRs compared to untreated rats (14.7±0.2 AU and 13.9±0.3 AU vs 18.1±0.9 AU, respectively; p<0.05). In conclusion equieffective antihypertensive dose of ALK or RAM improved oxidative stress and reduced M/L of mesenteric arteries. Only ALK increased the eNOS bioavailability. Hence, in dTGRs renin inhibition compares favorably to ACE inhibition in improving vascular remodeling.