Pharmacologic Perspectives of Functional Selectivity by the Angiotensin II Type 1 Receptor

The angiotensin II type 1 (AT(1)) receptorplays a key role in cardiovascular pathophysiology, and it is a major pharmacologic target in the treatment of many cardiovascular disorders. However, AT(1) receptor activation is also involved in adaptive responses to altered hemodynamic demands and to sudden injury occurring in the circulatory system. Hence, current drugs that block all AT(1) receptor actions most likely leave room for improvement. Recent developments show that two major signaling pathways used by the AT(1) receptor may be dissected by pharmacologic means. Key pathologic responses such as aldosterone secretion, vasoconstriction, and detrimental cardiac hypertrophy are known to result from G protein-dependent signal transduction, whereas G protein-independent mechanisms have beer? connected with more adaptive cardiac cell survival, migration, and regeneration phenotypes. Selective blockade of G protein actions and simultaneous activation of G protein-independent signaling could, therefore be desirable in certain situations. The previously unappreciated concept of "functional selectivity" makes this exact strategy feasible and. may yield improved drugs for cardiovascular therapy. (Trends Cardiovasc Med 2008; 18:305-312) (C) 2008, Elsevier Inc.