Persistent tissue converting enzyme inhibition following chronic treatment with Hoe498 and MK421 in spontaneously hypertensive rats

Abstract

Inhibition of angiotensin II generation in the plasma does not fully explain the antihypertensive effects of converting enzyme (CE) inhibitors. Thus, we investigated the role of CE inhibition in the tissue for the antihypertensive action of these drugs. After discontinuation of 4 weeks of oral treatment with either Hoe498 (3 mg/kg/day) or MK421 (30 mg/kg/day) in spontaneously hypertensive rats (SHRSP), the reduced pressor response to intravenous angiotensin I was normalized within 1 day, although systolic and diastolic blood pressure remained decreased during a 1 week post-treatment follow-up period. Two weeks of oral treatment with Hoe498 (1 mg/kg/day) and MK421 (30 mg/kg/day) in SHRSP lowered blood pressure markedly and inhibited CE in the plasma (43% and 22%), lung (85% and 33%), kidney (76% and 76%), aortic wall (75% and 48%), and (with Hoe498) in the heart (55%). After drug discontinuation, blood pressure remained decreased for an additional 2 weeks, whereas plasma CE was normal or elevated during the follow-up period. However, tissue CE activity measured 1 week after drug withdrawal was still inhibited in the aortic wall (67% and 30%) and in the kidney (48% and 41%). These results support the hypothesis that the prolonged antihypertensive action of CE inhibitors may be related to persistent CE inhibition in tissues such as vascular wall and kidney. Further, the data support the importance of CE inhibition at target sites other than plasma and lung vascular endothelium.