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.
de Gasparo
M
M
Ciba-Geigy Ltd., Research Department, Pharmaceuticals Division, Basle, Switzerland.
Whitebread
S
S
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology; D002144:Callithrix; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D019808:Losartan; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013777:Tetrazoles / Q000378:metabolism* / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000068756:Valsartan
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D014633:Valine; D019808:Losartan