Peripheral vs. Central Blockade of the Renin- Angiotensin System in Spontaneously Hypertensive Rats: Comparison of Novel AT₁ Receptor Antagonist TCV-116 with Angiotensin Converting Enzyme Inhibitor Delapril

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In the present study, we evaluated the hemodynamic and metabolic profiles derived from oral administration of the angiotensin converting enzyme inhibitor, delapril 50mg/kg/day, and the non-peptide angiotensin II type I (AT₁) receptor antagonist, TCV-116 1mg/kg/day, for five days, to try to discriminate AT₁ receptor-related responses from the depressor properties of chronic treatment with delapril in spontaneously hypertensive rats (SHRs). Both TCV-116 and delapril oral administrations significantly decreased blood pressure without any changes in heart rate. Delapril induced dipsogenic response and natriuresis associated with augmentation of urinary catecholamine excretion, while TCV-116 did not cause any changes in these variables. Neither delapril nor TCV-116 changed urinary excretion of prostaglandin (PG) E2 and 6-keto PG F_1α. We also examined the effects of centrally administered angiotensin converting enzyme inhibitor and AT₁ receptor antagonist to determine the central role of these drugs.Either the active metabolite of delapril, delapril-M1 1 mg/kg/day, or the active form of TCV-116, CV-11974 0.1mg/kg/day, were administered intracerebroventricularly for five days. Both treatments significantly decreased the blood pressure, in association with augmentation of the baroreceptor reflex control of heart rate, in response to phenylephrine injection. These findings suggest that the depressor properties of orally administered delapril are more complex than those of TCV-116, while central blockade by both angiotensin converting enzyme and AT₁ receptor decreases blood pressure in part through baroreceptor sensitization. (Hypertens Res;1993 16: 239-246)