Metabolic syndrome, a cluster of risk factors that increase the risk of cardiovascular morbidity and mortality, is common in patients with hypertension. Chronic renin-angiotensin-aldosterone system (RAAS) activation, shown by elevated plasma renin activity (PRA), is implicated in many of the features of metabolic syndrome. The direct renin inhibitor aliskiren may be of benefit in this patient group as aliskiren targets the RAAS at the rate-limiting step. In this double-blind study, 141 patients with hypertension (mean baseline BP 155/93 mm Hg) and metabolic syndrome (modified National Cholesterol Education Program ATP III criteria) were randomized to aliskiren 300 mg or irbesartan 300 mg once daily. Patients treated with aliskiren 300 mg had their mean sitting blood pressure (BP) lowered by 13.8/ 7.1 mm Hg after 12 weeks, significantly greater (Pp0.001) than the 5.8/2.8 mm Hg reduction observed in patients treated with irbesartan 300 mg. A significantly greater proportion of patients treated with aliskiren achieved BP control to o135/85 mm Hg (29.2 vs 16.7% with irbesartan; P ¼ 0.019). Aliskiren treatment led to a 60% decrease in PRA from baseline, whereas irbesartan increased PRA by 99% (both Po0.001). Aliskiren and irbesartan had similar effects on glucose and lipid profiles and on a panel of biomarkers of inflammation and cardiovascular risk. Both aliskiren and irbesartan were well tolerated. Collectively, these results suggest that aliskiren 300 mg may offer treatment benefits compared with irbesartan 300 mg for BP reduction in patients with hypertension and metabolic syndrome.
Background: Studies in transgenic rats expressing the human (pro)renin receptor have shown elevated plasma aldosterone levels in these animals despite unaffected plasma renin concentration or activity. It has been speculated that this is mediated through a direct effect of (pro)renin on aldosterone synthesis via the (pro)renin receptor ((P)RR). Other studies have shown an increased expression of adrenal CYP11B2 mRNA in these animals compared to wildtype despite unchanged levels of angiotensin II (Ang II). We evaluated the effect of (pro)renin on the expression of the main steroidogenic enzymes in an adrenocortical cell line (H295R).Methods: First, the expression of the (P)RR was tested by RT-PCR. Second, H295R cells (10^5 cells/mL) were serum-starved for 24 hours and subsequently incubated with Ang II (100 nM), phorbol-12-myristate-13-acetate (PMA, 10 nM), renin (1 and 10 nM), or prorenin (1 nM) for 6, 24 and 48 hours. After RNA isolation by standard methods, the expression of STAR, CYP11A1, HSD3B2, CYP21A2, CYP11B2, and CYP17A1 was measured by quantitative RT-PCR. To investigate whether an effect on aldosterone synthesis could be attributed to activation of the local renin-angiotensinsystem (RAS), ACE activity in H295R cells was assessed by measurement of Ang II formation after incubation with Ang I (10-8 M for 30, 60, 180 and 360 minutes).
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