Is Tissue Converting Enzyme Inhibition a Determinant of the Antihypertensive Efficacy of Converting Enzyme Inhibitors? Studies with the Two Different Compounds, Hoe498 and MK421, in Spontaneously Hypertensive Rats

Abstract

The mechanism of antihypertensive action of converting enzyme (CE) inhibitors was studied by comparing 2 different potent compounds. Spontaneously hypertensive rats (SHRSP) were treated orally with the CE inhibitors Hoe498 and MK421 for periods of 2 and 4 wk. The threshold antihypertensive dose of Hoe498 was below 0.1 mg/kg per day of MK421 1 mg/kg per day. Blood pressure was normalized with 10 mg/kg per day Hoe498 and 30 mg/kg per day MK421. The pressor response reduction to i.v. angiotensin I (ANG I), the potentiation of the bradykinin depressor responses and the decreases of the bradykinin depressor responses and the decreases of plasma angiotensin II levels or urinary aldosterone excretion were not correlated to the antihypertensive potency of the drugs. However, following equi-dose treatment (10 mg/kg per day) with both compounds of tissue CE activity inhibition in the vascular wall of the aorta, lung, kidney and brain cortex was more marked with Hoe498 than with MK421. Hoe498 also reduced CE activity in the heart, adrenal gland and in other brain areas, and attenuated the pressor responses to intracerebroventricularly injected ANG I. These results are the 1st direct evidence for tissue CE inhibition following chronic oral CE inhibitor treatment. Inhibition of the enzyme in target organs as vascular wall, kidney, heart or brain may be involved in the antihypertensive action of these drugs.