Comparative antihypertensive activities of losartan and HM70186 in rats with hepatic dysfunction.
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.
Choi
Jae-Hong
JH
College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, 361-763, Korea.
Shin
Sunhee
S
Park
Dongsun
D
Jeon
Jeong Hee
JH
Choi
Bong Ho
BH
Jang
Min-Jung
MJ
Joo
Seong Soo
SS
Oh
Ki-Wan
KW
Hong
Jin Tae
JT
Suh
Kwee-Hyun
KH
Kim
Yun-Bae
YB
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
D000959:Antihypertensive Agents; C543480:HM70186; D000804:Angiotensin II; D002251:Carbon Tetrachloride; D019808:Losartan