Sartan-AT1 receptor interactions: in vitro evidence for insurmountable antagonism and inverse agonism.
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.
Van Liefde
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I
Department of Molecular and Biochemical Pharmacology, Institute for Molecular Biology and Biotechnology, Vrije Universiteit Brussel (VUB), Brussel, Belgium.
Vauquelin
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G
D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism*; D001667:Binding, Competitive; D006332:Cardiomegaly; D006801:Humans; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1