[PubMed] [Google Scholar] 38

[PubMed] [Google Scholar] 38. far been very well tolerated with the same placebo-like side-effect profile as the ARBs. It also does not inhibit bradykinin metabolism and does not cause a cough. The high affinity binding to renin concentrates aliskiren in the kidney, a unique property that holds particular promise for renal protection. hRPB14 The avid renal concentration may well explain the long half-life of 24 hours and the slow recovery of blood pressure after the drug has been discontinued.48 These properties should promote continuous 24h blood pressure control. POTENTIAL LIMITATIONS OF ALISKIREN As monotherapy aliskiren appears to be equally effective as an ACE Inhibitor or ARB in lowering blood pressure, but not more effective.43, 49C51 On average, ambulatory blood pressure falls by ~10/7 mmHg.47, 51 Why is it that blood pressure does not fall more with the more complete renin-angiotensin system inhibition provided by the direct renin inhibitor? Several explanations can be proposed,4 but the simplest is that the renin-angiotensin system is only one of many regulatory pathways contributing to hypertension. The modest blood pressure reduction with aliskiren monotherapy most likely reflects compensation. Regardless of the precise explanation, aliskiren is not going to eliminate the need for multi-drug regimens to control most cases of hypertension, nor is it expected to be a magic bullet for resistant hypertension. There are other limitations that should be noted. The maximal daily dose is capped at 300 mg because higher doses can produce diarrhea, which is presumably due to 98% of the drug not being absorbed from the gut.2 Absorption is further reduced if aliskiren is taken with a fatty meal, thereby compromising bioavailability. 52 When aliskiren is co-administered with furosemide, the peak furosemide m-Tyramine hydrobromide blood concentration is reduced by as much as 50%.52 As with all renin-angiotensin system inhibitors, serum potassium needs to be monitored regularly and pregnancy is an absolute contraindication. From a theoretical standpoint, two potential limitations could arise from aliskirens novel mechanism of action. First, the proximal renin-angiotensin system blockade reduces the concentration of multiple downstream intermediates that in rodent models have both accelerated and retarded hypertensive target organ disease.9, 16, 25, 53, 54 The net effect in patients is unknown. The second and more intriguing mechanistic consideration relates to renin secretion. With aliskiren, the reactive rise in renin secretion is greater than with an ACE Inhibitor or ARB, reflecting more complete renin-angiotensin system inhibition.4, 47 When aliskiren is combined with HCTZ or an ARB, the reactive rise in renin secretion is dramatic.4, 47 This compensation could limit the absolute decrease in plasma renin activity and attendant fall in blood pressure, because the enzymatic block by the direct renin inhibitor is not 100% but closer to 75%.4 Furthermore, high circulating levels of reninand its precursor (prorenin)may activate fibrotic signaling pathways by novel receptor-mediated mechanisms that are completely m-Tyramine hydrobromide independent of angiotensin II production and angiotensin II type 1 receptor stimulation.55C57 POTENTIAL EFFECTS OF ALISKIREN m-Tyramine hydrobromide ON (PRO)RENIN RECEPTOR ACTIVATION An emerging body of basic research indicates that prorenin can no longer be considered merely the inactive precursor of renin. Secreted by the juxtaglomerular cells, prorenin initially is inactive because a hinge covers the angiotensinogen binding site (Figure 6).44 Classically, prorenin is converted to renin by enzymatic cleavage of the hinge, thereby exposing the angiotensinogen catalytic site. The catalytic site can be exposed and prorenin fully activated by a nonenzymatic process in which the hinge swings open but is not cleaved.44 This process occurs when circulating prorenin binds to a recently discovered class of (pro)renin receptors in the heart, kidneys, and presumably other target organs.44, 58 By blocking the catalytic site of both renin and activated prorenin, the direct renin inhibitor should eliminate the generation of angiotensin I both in the systemic circulation and at the tissue level (Figure 6). Because prorenin circulates at levels that are 10C100 times higher than m-Tyramine hydrobromide renin,44 prorenin inhibition holds promise for enhanced end-organ protection. Open in a separate window Figure 6 Inhibition of both enzymatic and nonenzymatic activation of prorenin. Modified with permission from: Danser AH, Deinum J. Renin, prorenin and the putative (pro)renin receptor. 2005 November;46(5):1069C76. However, (pro)renin receptor activation.