title: Non-peptide angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor: effect on a renin-induced deficit of a passive avoidance response in rats.
abstract: Non-peptide receptor ligands with differential affinity for the angiotensin II-1 (AII-1) receptor (EXP3312, EXP3880) or the AII-2 receptor (PD123177) and an angiotensin converting enzyme (ACE) inhibitor captopril were evaluated for the ability to protect against a renin-induced performance deficit in a passive avoidance (PA) task in rats. The ability to retain a PA response was shown to decrease as the dose of intracerebroventricularly (i.c.v.) administered renin increased with maximal retention deficits occurring at 1.0 micrograms/5 microliters i.c.v. EXP3312 (1-100 micrograms/5 microliters i.c.v.) and EXP3880 (1-100 micrograms/5 microliters i.c.v.) produced dose-dependent increases in retention latencies when co-administered with renin. The peak effect dose (PED) for EXP3312 and EXP3880 was 3 and 30 micrograms i.c.v., respectively. In contrast, PD123177 was not effective in preventing the renin-induced decrease in retention across a broad range of doses (0.1-100 micrograms/5 microliters i.c.v.). Captopril (1-100 micrograms/5 microliters i.c.v.) also prevented the renin-induced performance deficit with a PED of 30 micrograms/5 microliters i.c.v. These results suggest that renin given i.c.v. produces a deficit in performance of a PA response in rats and that this effect can be attenuated by an ACE inhibitor, AII-1 receptor ligands, but not AII-2 receptor blocker.
authors.affiliation: Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
authors.forename: V J
authors.initials: VJ
authors.lastname: DeNoble
authors.forename: K F
authors.initials: KF
authors.lastname: DeNoble
authors.forename: K R
authors.initials: KR
authors.lastname: Spencer
authors.forename: A T
authors.initials: AT
authors.lastname: Chiu
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: P B
authors.initials: PB
authors.lastname: Timmermans
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000502:physiology; D012016:Reference Values; D012083:Renin / Q000008:administration & dosage / Q000494:pharmacology*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C066253:PD 123177; C073719:EXP3312; C073721:EXP3880; D002216:Captopril; D012083:Renin