Sartan-AT1 receptor interactions: in vitro evidence for insurmountable antagonism and inverse agonism

• Published in: Molecular and cellular endocrinology 2009-04, Vol.302 (2), p.237-243
• Main Authors: Van Liefde, I, Vauquelin, G
• Format: Article
• Language: English
• Subjects: Angiotensin II Type 1 Receptor Blockers - metabolism; Binding, Competitive; Cardiomegaly; Humans; Receptor, Angiotensin, Type 1 - drug effects; Receptor, Angiotensin, Type 1 - metabolism
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2008.06.006

Sartans are non-peptide AT(1) 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 approximately equal EXP3174>valsartan>irbesartan>>losartan. When AT(1) 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.