¹State University of New York Downstate College of Medicine, Brooklyn, NY.

^*This activity is supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation.

Abstract

The physiologic function of the renin-angiotensin system (RAS) is to maintain fluid volume and blood pressure (BP) through aldosterone secretion, vasoconstriction, tubular sodium retention, and vasopressin release. Chronic activation of the RAS, however, produces injurious effects, including vascular endothelial dysfunction, cell growth and migration, extracellular matrix synthesis, inflammation and oxidation, and platelet aggregation, and plays an integral role in the development and progression of cardiovascular (CV) and renal disease. Furthermore, the RAS activates the sympathetic nervous system (SNS), itself a contributor to CV and renal disease. Renin-angiotensin system suppression with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II (Ang II) receptor blockers (ARBs) significantly reduces BP and CV morbidity and mortality. Cardiovascular morbidity and mortality remain high, and CV disease remains the number one killer, however, despite widespread use of ACEIs and ARBs. Further strategies to inhibit the RAS are clearly needed.

Angiotensin-converting enzyme inhibitors block ACE from converting angiotensin I (Ang I) to Ang II. They also block bradykinin degradation, leading to beneficial hemodynamic effects, but often causing cough and, more rarely, angioedema. Angiotensin II can also be generated by non-ACE pathways, such as chymase and cathepsin G. In fact, Ang II levels have been shown to return to pretreatment levels—so called "angiotensin II escape"— with long-term ACEI therapy. Through compensatory feedback mechanisms, plasma renin activity (PRA) increases with ACEI use, serving to activate the RAS and potentially overwhelm the ability of ACEIs to inhibit the RAS. Importantly, PRA is correlated with CV disease and is a predictor of disease progression and events. Angiotensin receptor blockers block the binding of Ang II to the angiotensin II type 1 receptor. The resulting decrease in Ang II activity, however, inactivates a negative short-loop feedback mechanism, resulting in increased renin secretion and elevated PRA. Thus, both ACEIs and ARBs are potentially self-limiting since RAS blockade may not be complete with chronic use of either class of agents.

Other antihypertensive agents directly or indirectly activate the RAS and/or the SNS. Beta-blockers inhibit renin release by blocking beta-adrenergic receptors at the renal nerve, only 1 of 4 triggers of renin secretion. The long-term action of thiazide diuretics likely involves vasodilation, but initially they increase urinary sodium excretion by inhibiting the sodium chloride pump, causing reductions in fluid volume, cardiac preload, and cardiac output. Accompanying water and salt loss activate both the RAS and the SNS. Calcium channel blockers (CCBs) cause vasodilation and reduction of peripheral resistance by blocking calcium-ion flow into smooth muscle and the myocardium. Dihydropyridine CCBs provoke increases in heart rate, SNS activity, and renin release. With prolonged use, heart rate returns to pretreatment levels, but SNS activity remains elevated. The effects of nondihydropyridine CCBs vary, with verapamil maintaining normal or reduced sympathetic activity, and diltiazem, normal or elevated activity. Direct vasodilators such as hydralazine can cause sodium and water retention, potentially activating both the SNS and RAS.

Renin inhibitors represent a new mechanism for suppressing the RAS. Renin inhibitors block renin from cleaving angiotensinogen into Ang I; this action occurs earlier in the RAS cascade compared with ACEI and ARB blockade. Since ACEIs and ARBs trigger marked increases in PRA, combination of ACEIs or ARBs with specific inhibitors of PRA may optimize RAS suppression. In fact, the first renin inhibitor to become available for clinical use, aliskiren, has been demonstrated to eliminate the rise in PRA seen with ARB monotherapy. Further investigation of the clinical benefits of combination therapy with renin inhibitors plus ACEIs or ARBs is needed.