Angiotensin II Receptor Blockers in the Treatment of Heart Failure

Ross C. Peterson, MD, Mark E. Dunlap, MD


CHF. 2002;8(5) 

In This Article

Role of the RAAS in the Pathophysiology of Heart Failure

In heart failure with a low cardiac output state, activation of the RAAS serves as a compensatory mechanism to maintain cardiac output. Reduced renal blood flow and sodium delivery to the distal tubule leads to renin release, which is exacerbated further by increased sympathetic tone.[9] Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I.[10] In turn, ACE cleaves angiotensin I to form the active octapeptide angiotensin II.[11] While the majority of ACE in the body is found in the pulmonary vasculature,[12] there is increasing evidence for local RAAS systems at the tissue level,[13,14] especially in the heart, kidneys, and vasculature.[13,15] Tissue production of angiotensin II may play a more important role in the progression of heart failure than circulating angiotensin II.

In addition to ACE-mediated conversion of angiotensin I, several alternative pathways lead to production of angiotensin II. Angiotensin II can be formed directly from angiotensinogen by the actions of elastase, cathepsin G, and tissue plasminogen activator.[16] Angiotensin I also can be converted to angiotensin II at the tissue level by chymase and cathepsin G.[17,18] The importance of these local pathways is underscored by the fact that tissue levels of angiotensin II are nearly 1000 times greater than levels in the circulation.[19]

Angiotensin II acts as a potent vasoconstrictor that serves to increase peripheral vascular resistance and maintain arterial tone in the face of reduced cardiac output. Angiotensin II also enhances release of catecholamines from noradrenergic nerve endings[20] and directly stimulates the adrenal cortex to increase secretion of aldosterone.[21] Aldosterone acts in the distal nephron to increase sodium and water retention and excrete potassium. Angiotensin II also has cellular effects that promote growth factors, migration, proliferation, and hypertrophy of vascular smooth muscle cells and cardiac fibroblasts.[22,23] While these mechanisms serve initially to maintain cardiac output, over time they become maladaptive and lead to progression of heart failure.

Renin-angiotensin-aldosterone system (RAAS) and site of action of angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors t-PA=tissue plasminogen activator; AT=angiotensin II receptor; ACE=angiotensin-converting enzyme; ARBs=angiotensin receptor blockers

ACE inhibitors have no effect on angiotensin II formed by alternate pathways. In contrast, ARBs would be expected to inhibit the biologic effects of angiotensin II more completely than ACE inhibitors, since they block the pathway more distally at the level of the receptor, whether the angiotensin II is formed by ACE- or non-ACE-mediated pathways.

Angiotensin II exerts its effects through stimulation of receptors that are located in a variety of tissues. The two angiotensin II receptor subtypes described best are designated AT1 and AT2.[24] The majority of the known effects of angiotensin II appear to be mediated through the AT1 receptor.[24,25,26] While the function of the AT2 receptor subtype has not been elucidated entirely, evidence from animal studies suggests that activation of this receptor subtype mediates vasodilation, inhibition of cell proliferation, and apoptosis.[27] Thus, the actions of AT2 receptor stimulation counterbalance the actions of the AT1 receptor. Moreover, AT2 expression may be up-regulated in certain disease states, such as heart failure and myocardial infarction.[28]

Blocking activation of the AT1 receptor might be expected to exert beneficial effects via mechanisms that could be additive to the effects of ACE inhibition. The direct effect would inhibit the maladaptive processes mediated by angiotensin II. In addition, blocking the AT1 receptor leads to increased levels of plasma renin activity and increased angiotensin II production through loss of feedback inhibition on renin production.[29] The elevated angiotensin II then would be available to stimulate the AT2 receptor. The significance of this effect in humans remains unknown, and there are conflicting results in animal studies regarding the importance of this mechanism.[30,31]