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Sartan–AT1 receptor interactions: In vitro evidence for insurmountable antagonism and inverse agonism

2008; Elsevier BV; Volume: 302; Issue: 2 Linguagem: Inglês

10.1016/j.mce.2008.06.006

1872-8057

Isabelle Van Liefde, Georges Vauquelin,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

Sartans are non-peptide AT1 receptor antagonists used to treat hypertension and related pathologies. Their effects on the G protein-dependent responses of angiotensin II (Ang II) were the same in vascular tissues and in isolated cell systems. All are competitive but, when pre-incubated, they act surmountably (only rightward shift of the Ang II concentration–response curve) or insurmountably (also decreasing the maximal response). Insurmountable behaviour reflects the formation of tight sartan–receptor complexes; it is often partial due to the co-existence of tight and loose complexes. Their ratio positively correlates with the dissociation half-life of the tight complexes and depends on the sartan: i.e. candesartan > olmesartan > telmisartan ≈ EXP3174 > valsartan > irbesartan ≫ losartan. When AT1 receptors display sufficient basal activity (in case of receptor over-expression, mutation and, especially, tissue stretching) sartans may also act as inverse agonists. This rather affects long-term, G protein-independent hypertrophic responses leading to cardiovascular remodelling.