title: In vivo pharmacology of DuP 753.
abstract: A review of the in vivo pharmacology of DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biphen yl-4- yl)methyl]imidazole, potassium salt) is presented. In the pithed rat, DuP 753 exerted a selective and competitive inhibition of the pressor response to angiotensin II (AII). In conscious normotensive rats, DuP 753 inhibited the AII-induced aldosterone secretion and drinking response. DuP 753 lowered blood pressure in conscious normotensive rats pretreated with furosemide but not in untreated normotensive rats. Unlike saralasin, DuP 753 given intravenously did not cause pressor response. In conscious renal hypertensive rats (RHRs), a high renin model, DuP 753 decreased blood pressure with an intravenous ED30 of 0.78 mg/kg and an oral ED30 of 0.59 mg/kg. The antihypertensive efficacy of DuP 753 in RHRs was similar to that of captopril. In DOCA hypertensive rats, a low renin model, DuP 753 did not lower blood pressure. In conscious 18- to 21-week-old spontaneously hypertensive rats (SHRs), DuP 753 given orally or intravenously reduced blood pressure dose-dependently and did not alter heart rate at these doses. The acute antihypertensive efficacy of DuP 753 was greater than that of captopril in SHRs. In contrast, DuP 753 and captopril given orally at 10 mg/kg/day for 15 days in SHRs caused a similar decrease in blood pressure. Bilateral nephrectomy but not inhibition of prostaglandin synthesis abolished the antihypertensive effect of DuP 753 in SHRs. Our study, therefore, indicates that DuP 753 is an orally active, nonpeptide, selective, and competitive AII receptor antagonist lacking agonism. It appears that there is a relationship between basal renin level and the acute antihypertensive effect of DuP 753 in rats. Further, our results suggest that the renin-angiotensin system plays a significant role in the control of blood pressure in conscious SHRs.
authors.affiliation: Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: W A
authors.initials: WA
authors.lastname: Price
authors.forename: A T
authors.initials: AT
authors.lastname: Chiu
authors.forename: J V
authors.initials: JV
authors.lastname: Duncia
authors.forename: D J
authors.initials: DJ
authors.lastname: Carini
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
authors.forename: A L
authors.initials: AL
authors.lastname: Johnson
authors.forename: P B
authors.initials: PB
authors.lastname: Timmermans
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D000959:Antihypertensive Agents; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D051381:Rats; D012016:Reference Values; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan