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.

CI-926 (3-[4-[4-(3-methylphenyl)-1-piperazinyl]butyl]-2,4-imidazolinedione): antihypertensive profile and pharmacology.

CI-926 (10(-7)-10(-6) M) selectively antagonized the contraction of isolated rabbit aortae to phenylephrine and displaced the alpha-1 adrenoceptor ligand WB4101 (IC50: 82 nM) in rat brain. In the spontaneously hypertensive rat, single oral doses of either CI-926 (0.3-10 mg/kg) or prazosin (0.3-100 mg/kg) caused dose-related reductions in blood pressure; however, CI-926 was more efficacious. The maximal antihypertensive response to CI-926 was unchanged with three consecutive days of oral dosing in the spontaneously hypertensive rat, whereas a first dose effect was noted with prazosin. In two-kidney, one-clip, renal hypertensive rats, CI-926 and prazosin (1-10 mg/kg) lowered blood pressure; however, prazosin was more efficacious. In perinephritic hypertensive dogs, CI-926 (10 mg/kg) lowered blood pressure 20%. In anesthetized dogs, CI-926 in the presence of supermaximal blood pressure-lowering doses of prazosin caused an additional reduction in pressure. With equivalent alpha-1 blockade in anesthetized rats, CI-926 tended to have greater hypotensive activity than prazosin. These results demonstrate that CI-926 is a potent, orally active antihypertensive agent in renin-dependent and -independent hypertension. The profile of CI-926 suggests that it lowers blood pressure in part by interacting with peripheral alpha-1 adrenoceptors and in part via an additional mechanism(s). Although weak relative to its affinity for alpha-1 adrenoceptors, CI-926 was found in preliminary experiments to interact with alpha-2 adrenoceptors, serotonergic receptors and dopaminergic receptors. The importance of these interactions to the blood pressure response of CI-926 remains to be elucidated.