DuP 753 is a potent nonpeptide antagonist of angiotensin II receptors in isolated perfused rat kidney and cultured renal cells.
In the present study we investigated the antagonist action of DuP 753 (2-n-butyl-4-chloro-5-hydroxy-methyl-1-[2'-(1H-tetrazol-5-yl)biphe nyl-4-yl) methyl]imidazole, potassium salt) on angiotensin II (AII) binding and vascular effects in the isolated perfused rat kidney. In addition, we determined binding of DuP 753 in cultured glomerular mesangial cells and renomedullary interstitial cells. In the isolated kidney, DuP 753 fully displaced AII from its specific binding sites with high affinity (IC50 = 200 nmol/L) and antagonized the vasoconstrictive effect of AII in a dose-related manner with an ED50 of 170 nmol/L. These effects of DuP 753 were qualitatively similar to those of saralasin and the antagonist effect of DuP 753 on AII-induced renal vasoconstriction was fully overcome by excess AII. DuP 753 had no effect on its own on renal vascular resistance. In cultured glomerular mesangial cells and renomedullary interstitial cells, DuP 753 fully inhibited the specific binding of [125I]-Sar-AII at 1 mumol/L with IC50s of 6.7 and 11 nmol/L for glomerular mesangial cells and renomedullary interstitial cells, respectively. The present results demonstrate that a novel imidazole derivative, DuP 753, is a powerful non-peptide antagonist of angiotensin II receptors in isolated perfused rat kidney and in cultured glomerular mesangial and renomedullary interstitial cells.
Fontoura
B M
BM
Department of Physiology, Cornell University Medical College, New York, NY 10021.
Nussenzveig
D R
DR
Timmermans
P B
PB
Maack
T
T
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000187:drug effects*; D019808:Losartan; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D012504:Saralasin / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013777:Tetrazoles; D012504:Saralasin; D019808:Losartan