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Binding of KRH‐594, an antagonist of the angiotensin II type 1 receptor, to cloned human and rat angiotensin II receptors
Author(s) -
Inada Y.,
Nakane* T.,
Chiba S.
Publication year - 2002
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1046/j.1472-8206.2002.00076.x
Subject(s) - angiotensin ii , receptor , endocrinology , antagonist , chemistry , angiotensin receptor , medicine , renin–angiotensin system , angiotensin ii receptor type 1 , pharmacology , biology , biochemistry , blood pressure
We studied the binding properties of KRH‐594, a new selective antagonist of angiotensin II (AII) type 1 (AT 1 ) receptors, to rat liver membranes and to recombinant AT 1 and AT 2 receptors. Preincubation of rat liver membranes with KRH‐594 produced maximal inhibition of [ 125 I]‐AII binding when the preincubation time was 1–2 h. Preincubation with KRH‐594 for 2 h decreased the B max value and increased the K d value. For human AT 1 , human AT 2 , rat AT 1A and rat AT 1B receptors, the K i values for KRH‐594 were 1.24, 9360, 0.67, and 1.02 n m , respectively. The rank order of K i values for human AT 1 receptors was KRH‐594 >> EXP3174 > candesartan=AII. The order of specificities for human AT 1 and AT 2 receptors was candesartan > EXP3174 > KRH‐594. Although a 2‐h preincubation of human AT 2 receptors with KRH‐594 (30 µ m ) or CGP 42112 (a selective AT 2 receptor antagonist; 0.3 n m ) inhibited binding of [ 125 I]‐AII, the suppression by KRH‐594 was not significant. These results indicate that KRH‐594 binds potently to AT 1 receptors in an insurmountable manner, and that at a very high dose (30 µ m ) it may also bind to AT 2 receptors, but in a surmountable manner.