title: Comparative antihypertensive activities of losartan and HM70186 in rats with hepatic dysfunction.
abstract: HM70186, a medoxomil ester of EXP3174 which is an active metabolite of angiotensin II receptor blocker losartan, was synthesized, and its antihypertensive efficacy was evaluated in rats with hepatic dysfunction. Male Wistar rats were intraperitoneally injected with 0.5 mL/kg of carbon tetrachloride to cause hepatic injury, and implanted with an osmotic minipump containing angiotensin II (0.4 mg/kg/day) to induce hypertension. After confirmation of both hepatic damage and hypertension, the rats were orally administered losartan or HM70186, and then blood pressure and heart rate were monitored for 24 h. In normal animals, angiotensin II-induced hypertension was lowered by losartan, resulting in an ED(-30 mmHg) of 9.05 mg/kg. HM70186 also immediately decreased the blood pressure in a dose-dependent manner, exhibiting an ED(-30 mmHg) of 0.89 ng/kg (10,000 times the potency observed with losartan). Moreover, HM70186 (3 ng/kg) exerted a strong antihypertensive effect even in rats with hepatic injury, while losartan (10 microg/kg) was ineffective. These results suggest that HM70186 could be a promising candidate for the treatment of hypertension accompanied by hepatic dysfunction.
authors.affiliation: College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, 361-763, Korea.
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Choi
authors.forename: Sunhee
authors.initials: S
authors.lastname: Shin
authors.forename: Dongsun
authors.initials: D
authors.lastname: Park
authors.forename: Jeong Hee
authors.initials: JH
authors.lastname: Jeon
authors.forename: Bong Ho
authors.initials: BH
authors.lastname: Choi
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Jang
authors.forename: Seong Soo
authors.initials: SS
authors.lastname: Joo
authors.forename: Ki-Wan
authors.initials: KW
authors.lastname: Oh
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.forename: Kwee-Hyun
authors.initials: KH
authors.lastname: Suh
authors.forename: Yun-Bae
authors.initials: YB
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008107:Liver Diseases / Q000473:pathology / Q000503:physiopathology*; D019808:Losartan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000959:Antihypertensive Agents; C543480:HM70186; D000804:Angiotensin II; D002251:Carbon Tetrachloride; D019808:Losartan