Pharmacologic perspectives of functional selectivity by the angiotensin II type 1 receptor

TY - JOUR

T1 - Pharmacologic perspectives of functional selectivity by the angiotensin II type 1 receptor

AU - Aplin, Mark

AU - Christensen, Gitte Lund

AU - Hansen, Jakob Lerche

PY - 2008/11

Y1 - 2008/11

N2 - The angiotensin II type 1 (AT(1)) receptor plays 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 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.

AB - The angiotensin II type 1 (AT(1)) receptor plays 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 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.

KW - Aldosterone

KW - Angiotensin II

KW - Angiotensin II Type 1 Receptor Blockers

KW - Cardiomegaly

KW - Cardiovascular Diseases

KW - Feasibility Studies

KW - GTP-Binding Proteins

KW - Humans

KW - Receptor, Angiotensin, Type 1

KW - Renin-Angiotensin System

KW - Signal Transduction

U2 - 10.1016/j.tcm.2009.01.003

DO - 10.1016/j.tcm.2009.01.003

M3 - Journal article

C2 - 19345318

SN - 1050-1738

VL - 18

SP - 305

EP - 312

JO - Trends in Cardiovascular Medicine

JF - Trends in Cardiovascular Medicine

IS - 8

ER -