Binding of valsartan to mammalian angiotensin AT1 receptors

The binding characteristics of the angiotensin AT1 receptor antagonist valsartan were investigated in different animal species and tissues. Using [125I](Sar1,Ile8) angiotensin II as radioligand, affinity constants were determined in liver and adrenal rat and marmoset, human adrenal and in rat aortic smooth muscle cells. In all tissues tested, valsartan had a greater affinity for the AT1 receptor than losartan (on average 5-fold). The affinities of both antagonists were up to 30 times weaker in the dog tissues [3H]Valsartan bound with high affinity (Kd 1.44 nmol/l) to the rat aortic smooth muscle cell AT1 receptor. Binding was saturable and reversible. Non-specific binding was low (10%). Reports that [3H]losartan binds to a non-angiotensin II binding site in rat liver and in other tissues could be confirmed. [3H]Valsartan on the other hand bound only to the AT1 receptor. Using a competition binding assay with [3H]losartan on rat liver membranes it could be shown that valsartan can bind to the 'losartan binding site', but at a 10,000-fold less affinity than for the AT1 receptor. Valsartan is therefore a highly specific and selective antagonist of the AT1 receptor. Due to its high affinity and low non-specific binding it is a suitable radioactive antagonist for the study of the distribution and function of the angiotensin AT1 receptor.