Renal hemodynamic and excretory responses to PD 123319 and losartan, nonpeptide AT1 and AT2 subtype-specific angiotensin II ligands.
Angiotensin receptor subtypes have been described and pharmacologically characterized. DuP 753 (losartan) selectively antagonizes the angiotensin type 1 receptor, whereas PD 123319 selectively binds to an angiotensin type 2 receptor. These studies compared the renal response to treatment with the nonpeptides, DuP 753 and PD 123319, and the peptide antagonist, saralasin, in anesthetized mongrel dogs. Saralasin and DuP 753 increased renal blood flow and were mildly natriuretic. DuP 753 was roughly 10-fold less potent than saralasin. PD 123319 had no effect on renal hemodynamics, but produced dose-related increases in urine volume and free water clearance. PD 123319 had no effect on circulating vasopressin levels, suggesting the change in water handling by the kidney was not due to inhibition of vasopressin release. A direct effect of PD 123319 at the level of the renal tubule has not been ruled out. This is the first report of a renal functional response to an angiotensin type 2 receptor ligand and suggests that the angiotensin type 2 receptor may be related to water handling by the kidney.
Keiser
J A
JA
Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan.
Bjork
F A
FA
Hodges
J C
JC
Taylor
D G
DG
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D019808:Losartan; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D012079:Renal Circulation / Q000187:drug effects*; D012504:Saralasin / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D012504:Saralasin; D019808:Losartan