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

The angiotensin II type 1 (AT₁) receptor plays a key role in cardiovascular pathophysiology, and it is a major pharmacologic target in the treatment of many cardiovascular disorders. However, AT₁ 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 AT₁ receptor actions most likely leave room for improvement. Recent developments show that two major signaling pathways used by the AT₁ 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 or -independent signal transduction, whereas mechanisms have been connected with more adaptive cardiac cell survival, migration, and regeneration phenotypes. Selective blockade of G protein actions and simultaneous activation of G protein-dependent or -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.

Abbreviations: 7TM, seven-transmembrane, AngII, angiotensin II, AT₁, Angiotensin II type 1, ERK1/2, extracellular signal-regulated kinases 1 and 2, PKC, protein kinase C, [SII] AngII, [sarcosine¹, isoleucine⁴, isoleucine⁸] AngII