that aliskiren as monotherapy effectively reduces blood pres- sure in a dose-dependent fashion in doses of 75–600 mg, its effect was similar regardless of age or gender. In summary, these clinical studies show that once-daily administration of aliskiren effectively lowers BP, being at least as effective as or possibly more effective than standard doses of established ACE inhibitors and ARBs. The long half-life of aliskiren can be expected to provide more reliable continuous BP control through the morning surge of BP that is known to be associated with increased cerebrovascular events (Kario et al 2003). Also, aliskiren possesses synergistic poten- tial when combined with a thiazide diuretic, an ACE inhibitor, a calcium antagonist, and possibly also with an ARB. Target organ protection with aliskiren There is considerable evidence that inhibition of RAAS in essential hypertension is associated with prevention of cardiovascular complications (Dahlöf et al 2002, 2005; Julius et al 2004). However, in all these studies (and several others), the interpretation of the results has been difﬁcult with regard to identifying the beneﬁts that go beyond those of BP reduction per se. Moreover, it has been suggested that blood pressure lowering is the major determinant of cardiovascular events in primary and secondary prevention trials and the dif- ferences in outcomes can be ascribed to small differences in achieved systolic blood pressure (Staessen et al 2005; Wang et al 2005). Similarly, a recent meta-analysis of 127 clinical trials questioned the speciﬁc renoprotective effects of ACE inhibitors and ARBs beyond the effect related to blood pres- sure lowering (Casas et al 2005). However, even though the underlying mechanisms of achieving cardiovascular protection may not be completely understood, establishing a new antihypertensive drug as a valuable addition to current therapeutic options requires proof of beneﬁcial effects on mortality and morbidity. There is no long-term data available yet for aliskiren from studies with hard endpoints, but certain characteristics of the drug may point to cardioprotective and renoprotective properties. The potential renoprotective effects of renin inhibitors were suggested already based on the studies with the earlier com- pounds. Studies on renal vasodilation with enalkiren and zankiren showed that renin inhibitors induce renal vasodilation to a greater extent than ACE inhibitors, despite the expectation that ACE inhibition might be superior due to additionally inducing vaso- dilation through kinin generation (Hollenberg et al 1998). These studies indicate that renin inhibitors might confer renoprotection possibly to larger extent than the ACE inhibitors. Vascular Health and Risk Management 2007:3(6) Aliskiren in essential hypertension Pilz et al studied aliskiren in relation to target-organ damage in the double transgenic rat model comparing the effects of aliskiren (0.3 mg/kg/day and 3 mg/kg/day) and valsartan (1 mg/kg/day and 10 mg/kg/day) with no treatment (Pilz et al 2005). Both aliskiren doses and the high valsartan dose lowered blood pressure and albuminuria more effectively than the low valsartan dose. Aliskiren and valsartan in high dose ameliorated markedly left ventricular hypertrophy. After 3-weeks, none of the untreated rats had survived, compared with 74% of the low-dose valsartan group, and 100% in all other groups (ie, high-dose valsartan and both aliskiren doses). In this animal model, renin inhibition therefore compared favourably with AT1-receptor blockade in reversing target-organ damage. It has been speculated that direct inhibition of renin might have further advantage in cardiovascular protection by preventing activation of speciﬁc renin receptors (Azizi et al 2006). The renin receptor was identiﬁed in 1996 in the glomerular mesangium cells (Nguyen et al 1996), the receptor is also present in the subendothelium of coronary and renal arteries. Renin was found to bind to this receptor with high afﬁnity, but binding of renin to this receptor was not attenuated by renin inhibitors, indicating that the renin catalytic site is distinct from the receptor binding site. It was further elucidated that binding of renin to this receptor resulted in signiﬁcant increase in its catalytic efﬁciency in Ang I formation (Nguyen et al 2002). Receptor-bound renin will also induce a series of intracellular events that are distinct from the generation of Ang II. Moreover, this receptor also binds prorenin that, when bound to the receptor, would have renin-like action. Prorenin has been shown to be a powerful predictor of microvascular complications in diabetes mellitus, although the exact mechanism of this deleterious effect has not been elucidated (Fisher and Hollenberg 2005). It could be speculated that the activation of the renin receptor, in combination with the increased catalytic activity, might play a role in the pathogenesis of vascular complications, pointing to an attractive therapeutic potential for renin inhibition. Tolerability and safety Aliskiren has been shown to be well tolerated in healthy sub- jects and in patients with hypertension, when given as single and multiple oral doses. The incidence of adverse events with aliskiren and the number of study discontinuations as a result of adverse events during aliskiren treatment have been relatively low and were similar to results obtained in patients treated with wither placebo. The most common adverse effects reported were fatigue, headache, dizziness and diarrhoea (Stanton et al 2003, Gradman et al 2005; Weir et al 2006). 813