Protective effects of ME3221 on hypertensive complications and lifespan in salt-loaded stroke-prone spontaneously hypertensive rats.
1. A comparison was made on the protective effects of the following: ME3221, a competitive angiotensin AT1 receptor antagonist; losartan, in which a major active metabolite is a non-competitive angiotensin AT1 receptor antagonist; and enalapril, an angiotensin-converting enzyme inhibitor, using the salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP received orally ME3221 (3 and 10 mg/kg per day), losartan (10 mg/kg per day) and enalapril (10 mg/kg per day) from the 6th to the 20th week of age. All the control rats showed rapid elevation of systolic blood pressure (SBP), accompanied by hypertensive complications, and died by 15 weeks of age. 3. ME3221, losartan and enalapril suppressed the elevation of SBP in the salt-loaded SHRSP to a comparable degree. ME3221 and losartan increased the survival rate to > 90%, and diminished hypertensive complications such as cerebral apoplexy (stroke), renal injury (increased proteinuria, and total N-acetyl-beta-D-glucosaminidase activity) and heart failure (cardiac hypertrophy and pleural effusion). 4. Competitive (ME3221) and non-competitive (losartan) angiotensin AT1 receptor antagonists showed comparable efficacy against the complications and mortality of the salt-loaded SHRSP; both were more potent than enalapril in the protective effect.
Nagura
J
J
Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., Yokohama, Japan.
Yamamoto
M
M
Hui
C
C
Yasuda
S
S
Hachisu
M
M
Konno
F
F
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000627:therapeutic use; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000652:urine; D007093:Imidazoles / Q000627:therapeutic use*; D019808:Losartan; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013777:Tetrazoles / Q000627:therapeutic use*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; C093897:ME 3221; D013777:Tetrazoles; D004656:Enalapril; D019808:Losartan