Synthetic Phosphatidylethanolamines as Renin Inhibitors

Abstract

Summary

Anti-renin and hypotensive effects of synthetic PEs were examined.

(i) Eighteen PEs including optical isomers were newly synthesized. Arachidonic acid, linolenic acid, and stearic acid were substituted at the positions of β, γ, or both. Natural PE was extracted from porcine kidney, and the lyso form was prepared by treatment of phospholipase A.

(ii) Anti-renin activity of these compounds was determined using high-renin plasma obtained from the dog. The inhibition of renin activity was expressed as a percentage of the reduction in the production rate of angiotensin I as measured by radioimmunoassay.

(iii) The inhibitory effects of PE(β-C₁₈ ⁼³, γ-C₁₈) series, d- and DL-PE(β-C₂₀ ⁼⁴, γ-C₁₈), and dl- and l-PE(β-C₁₈, γ-C₂₀ ⁼⁴) were greater than that of the natural PE, but did not exceed the effect of lyso-PE.

(iv) Hypotensive effect was evaluated in conscious normotensive, spontaneously hypertensive, and renal hypertensive rats by daily im injection of the test compounds.

(v) Following repeated administration of natural PE, d-PE(β-C₁₈, γ-C₂₀ ⁼⁴), and d-PE(β-C₁₈, γ-C₁₈ ⁼³) to renal hypertensive rats, blood pressure decreased by more than 30 mm Hg. d- and DL-PE(β-C₁₈ ⁼³, γ-C₁₈ ⁼⁴), dl-PE (β-C₁₈, γ-C₁₈ ⁼), and dl-PE(β-C₁₈, γ-C₁₈ ⁼⁴) lowered pressure more than 40 mm Hg. dl-PE(β-C₁₈, γ-C₁₈ ⁼⁴) showed hypotensive effects both in renal hypertensive and spontaneously hypertensive rats, but not in normotensive rats.

The phospholipid compounds were synthesized and donated by Dainippon Pharmaceutical Co., Ltd. Thanks are also due to M. Ohara for preparing the manuscript.