Protective Effects of Me3221 on Hypertensive Complications and Lifespan in Salt‐loaded Stroke‐prone Spontaneously Hypertensive Rats

Abstract

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.

Enalapril Prevents Imminent and Reduces Manifest Cerebral Edema in Stroke-Prone Hypertensive Rats

“…3,4,8,9,11,12 No information is available on the effects of treatment with an ACE inhibitor in this model at a later and clinically more interesting stage, ie, after the manifestation of proteinuria, either when cerebral edema has appeared or at a stage of imminent cerebral edema. In our previous study we demonstrated with MRI that T2 prolongation identified cerebral edema in this model, and we were able to quantify the appearance and progression of cerebral edema.…”

Angiotensin inhibition and longevity: a question of hydration

“…The effect was reported first by Nagura and colleagues [82,83], showing that ME3221, a surmountable AT1 antagonist, prevented hypertensive complications and prolonged survival of salt-loaded or aged stroke-prone spontaneously hypertensive rats (SHR). Linz and his colleagues found that ramipril, an ACE inhibitor (ACEI), increased survival in old SHR and stroke-prone SHR, from 21 to 30 months of age, and at the same time, significantly reversed the established cardiac hypertrophy [65,67].…”

ME3221: A Novel Angiotensin II Receptor Antagonist

“…Findings indicated that the drug suppressed the elevation of systolic blood pressure (SBP) (by about 20 to 40 mm Hg) in salt-loaded SHRSP, increased the surviwal rate to more than 90% (Fig. 3), 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 cffusion) (6).…”

“…The drugs were administered once a day to the rats from 6 to 20 weeks of age. From ref 6. with permission.…”