The In Vitro Binding Properties of Non-Peptide AT1 Receptor Antagonists

Journal of Clinical and Basic Cardiology 2002; 5 (1): 75-82

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Keywords: Angiotensin II,  AT1-Rezeptor,  CHO-Zellen,  Angiotensin II,  AT1 receptor,  CHO cells,  insurmountable,  surmountable

A major breakthrough in the development of AT1 receptor antagonists as promising antihypertensive drugs, was the synthesis of potent and selective non-peptide antagonists for this receptor. In the present manuscript an overview of the in vitro binding properties of these antagonists is discussed. In particular, CHO cells expressing human AT1 receptors offer a well-defined and efficient experimental system, in which antagonist binding and inhibition of angiotensin II induced responses could be measured. From these studies it appeared that all investigated antagonists were competitive with respect to angiotensin II and bind to a common or overlapping binding site on the receptor. Moreover this model allowed us to describe the mechanism by which certain antagonists depress the maximal angiotensin II responsiveness in vascular contraction studies. Insurmountable inhibition was found to be related to the dissociation rate of the antagonist-AT1 receptor complex. The almost complete (candesartan), partially insurmountable inhibition (irbesartan, EXP3174, valsartan) or surmountable inhibition (losartan), was explained by the ability of the antagonist-receptor complex to adopt a fast and slow reversible state. The equilibrium between both states depends on the structure of the antagonist and determines the extent of insurmountable inhibition. In addition to the slow dissociation rate, the rebinding of certain antagonists (candesartan and EXP3174) as measurable in washout experiments, may contribute to a long-lasting blood pressure lowering effect in vivo.