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 -
