Pharmacologic perspectives of functional selectivity by the angiotensin II type 1 receptor.
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.
Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej, Denmark.
Mark
M
Aplin
Gitte Lund
GL
Christensen
Jakob Lerche
JL
Hansen
D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use*; D006332:Cardiomegaly / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D005240:Feasibility Studies; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction / Q000235:genetics
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000450:Aldosterone; D019204:GTP-Binding Proteins