2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- Azabicyclo[3.3.0]octane-3-carboxylic Acid (Hoe 498): Antihypertensive Action and Persistent Inhibition of Tissue Converting Enzyme Activity in Spontaneously Hypertensive Rats

The antihypertensive actions of the new converting enzyme (CE) inhibitors 2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl] -L-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) and enalapril were compared in spontaneously hypertensive rats (SHRSP), and their effects on tissue CE activity were investigated. Oral treatment with one single dose of the CE inhibitors Hoe 498 (1 mg/kg) and enalapril (30 mg/kg) in normotensive rats produced up to 24 h CE inhibition in plasma, aorta, heart and brain cortex and a 48 h inhibition of the enzyme in kidney and lung. In SHRSP, four-week oral treatment with Hoe 498 (0.1, 1, 10 mg/kg/day) and enalapril (1, 10, 30 mg/kg/day) lowered arterial blood pressure dose-dependently, with normalization of blood pressure following the respective highest dose. Plasma CE activity was inhibited during treatment with both drugs and increased or normal after drug withdrawal, while blood pressure remained decreased for 2-3 weeks post treatment. After 4 weeks of Hoe 498 (3 mg/kg/day) in SHRSP blood pressure was normalized and CE activity was markedly reduced in plasma, lung, kidney, aorta, mesenteric artery, heart, hypophysis and medulla oblongata. The CE inhibition persisted for one week in the kidney and mesenteric artery, accompanying the persistent post treatment blood pressure reduction. Our results demonstrate the strong antihypertensive potency of Hoe 498 in SHRSP and strengthen the hypothesis that CE inhibition in target tissues such as kidney and vascular wall is an important factor involved in the antihypertensive action of CE inhibitors.