Exploring New Mechanistic Pathways of the Renin Angiotensin System

Prof. Ferrario, Carlos M. Wake Forest University School of Medicine Hypertension and Vascular Disease Research Center, Medical Center Boulevard, Winston-Salem, NC 27157-1032, United States.

The receptors mediating the biological actions of angiotensin II (Ang II) have occupied the attention of researchers for the two last decades. The further characterization of the physiological actions of angiotensin-(1-7) [Ang-(1-7)], angiotensin converting enzyme 2 (ACE2) and the mas receptor established a new understanding of the role of the RAS in cardiovascular regulation by demonstrating that the ACE2/Ang-(1-7)/mas receptor axis functions as an endogenous inhibitor of the pressor and antiproliferative actions of Ang II.

More recently, the landmark introduction of the first orally active renin inhibitor, aliskiren, has provided a new tool to unravel the actions of Ang II in the regulation of cardiovascular function and afforded an improved approach to the control of blood pressure in hypertensive subjects. Both clinical and experimental studies now demonstrate that inhibition of renin improves blood pressure control in a large group of hypertensive subjects; the beneficial effects of direct renin inhibition occur in subjects of all ages and gender, different ethnic backgrounds, the obese, and those with associated pathology such as type 2 diabetes.

Clinical studies have confirmed the efficacy of aliskiren in controlling the blood pressure in essential hypertensive subjects with a potency equivalent to that found with optimal doses of other antihypertensive agents such as angiotensin converting enzyme (ACE) inhibitors, Ang II receptor blockers (ARBs), and calcium antagonists. But unlike those other drugs, aliskiren abrogates a reactive increase in plasma renin activity, a critical and often poorly understood consequence of the action of other antihypertensive agents including the thiazide diuretics. The inhibitory activity of aliskiren on plasma renin activity has led to the combination of the direct renin inhibitor with either thiazides or ARBs. These combinations have an additional additive antihypertensive effect that is not associated with increase in adverse events or a reactive rise in plasma renin activity.

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Ferrario, C.M., Trask, A.J. and Jessup, J.A. (2005) Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am J Physiol Heart Circ Physiol 289:H2281-H2290.
Ferrario, C.M. and Jessup, J.A. (2008) Renin Inhibitor Pharmacotherapy for Hypertension. Summit Communications, LLC: Armonk, NY.