Premium
Interaction between the partially insurmountable antagonist valsartan and human recombinant angiotensin II type 1 receptors
Author(s) -
Verheijen Ilse,
Fierens F.L.P.,
DeBacker J.P.,
Vauquelin G.,
Vanderheyden P.M.L.
Publication year - 2000
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 - 10.1111/j.1472-8206.2000.tb00443.x
Subject(s) - valsartan , angiotensin ii receptor type 1 , angiotensin ii , losartan , chemistry , competitive antagonist , candesartan , receptor , angiotensin receptor , pharmacology , renin–angiotensin system , endocrinology , irbesartan , medicine , antagonist , biology , biochemistry , blood pressure
— The interaction between the AT 1 receptor‐selective antagonist valsartan, and its human receptor, was investigated by direct radioligand binding as well as by its inhibition of angiotensin II induced inositol phosphate accumulation in CHO cells expressing human recombinant AT 1 receptors. Specific binding of [ 3 H]‐valsartan rapidly reached equilibrium at 37°C. It was saturable and occurred to a homogeneous class of sites with a K D of 0.88 ± 0.076. It was inhibited by other AT 1 receptor antagonists with the same potency order as previously described for the binding of [ 3 H]‐angiotensin II and [ 3 H]‐candesartan to human AT 1 receptors (i.e. candesartan ≥ EXP3I74 > valsartan ≅ irbesartan ≅ angiotensin II > losartan). When valsartan and angiotensin II were applied simultaneously to the CHO‐AT 1 cells, the antagonist caused a rightward shift of the angiotensin II concentration‐response curve. Hence, valsartan interacts with the AT 1 receptor in a manner that is competitive with angiotensin II. Pre‐incubation of the cells with 0.5, 5 and 50 nM valsartan caused an additional, concentration‐dependent, up to 55 % decline of the maximal response. The partial nature of this insurmountable inhibition by valsartan was confirmed by biphasic antagonist concentration‐inhibition curves. These data reflect the co‐existence of a fast reversible/surmountable as well as a tight binding/insurmountable valsartan‐receptor complex. In agreement, pre‐incubation of the CHO‐AT 1 cells with 5 and 50 nM valsartan produced a partial inhibition of the angiotensin II induced increase of the free intracellular calcium concentration. [ 3 H]‐Valsartan dissociated from its receptors with a half‐life of 17 min. In functional recovery experiments with valsartan‐pre‐treated cells, the angiotensin II‐mediated response was half‐maximally restored within approximately 30 min. These kinetic data suggest that the insurmountable inhibition by valsartan is related to its relatively slow dissociation from the human AT 1 receptors.