How to Explain the Differences Between Renin Angiotensin System Modulators

Angiotensin II (Ang II) plays important roles in the development of cardiovascular diseases including hypertension, renal diseases, cardiac hypertrophy, congestive heart failure, and ischemic heart disease. Angiotensin II exerts classic hemodynamic and renal effects, but it is also a local biologically active mediator with direct effects on endothelial and smooth muscle cells. Two subtypes of Ang II receptors, type 1 (AT1) and type 2 (AT2), have been identified. Their roles have been investigated in depth in vivo and in vitro, although few data are available concerning the role of the AT2 receptors in the adult circulation in humans. The two receptors, both of which belong to the superfamily of G-protein–coupled receptors, have different signaling pathways and different functions. The AT1 receptor subtype is expressed ubiquitously and is involved in most of the well-known biological functions of Ang II. The AT1 receptor transactivates growth pathways and mediates major Ang II effects such as vasoconstriction, increased cardiac contractility, renal tubular sodium reabsorption, cell proliferation, vascular and cardiac hypertrophy, inflammatory responses, and oxidative stress. In contrast to AT1, the physiologic role of AT2receptors has long remained an enigma. The AT2 receptors are highly expressed in fetal tissues, although their expression dramatically decreases after birth, being restricted to a few organs, including the cardiovascular system. The AT2 receptor is re-expressed in the adult animal after cardiac and vascular injury and during wound healing, suggesting a role for this receptor in tissue remodeling, growth, or development. Recent and concordant data suggested that overstimulation of AT2 receptors might be implied in cardiac and vascular hypertrophic processes. Both Ang II receptors are involved in hypoxia-induced neovascularization. A large set of experimental evidence suggests that activation of the AT1 receptor results in proangiogenic effects, whereas AT2 receptors mediate apoptosis and thus antiangiogenic effects. Furthermore, bradykinin through its B1 or B2 receptors is a potent activator of experimental hypoxia-induced neovascularization. Thus, pharmacologic blockade of the AT1 receptor and resulting overactivation of AT2 receptors could impair or delay neovascularization in ischemic tissues in patients receiving chronic treatment with angiotensin receptor blockers. In contrast, increased tissue bradykinin resulting from inhibition of converting enzyme could help to restore functional vascularization in ischemic tissues. These basic concepts deserve a second reading and reevaluation to discuss differences in vascular protection in large clinical trials with different classes of drugs acting on the renin-angiotensin system.