CONTINUOUS VERSUS INTERMITTENT ANGIOTENSIN-CONVERTING ENZYME-INHIBITION IN RENAL HYPERTENSIVE RATS

Converting enzyme inhibitors impair renal function of the kidney beyond a stenosis of the renal artery in humans and induce histological lesions in the clipped kidney of renal hypertensive rats. In two-kidney, one clip hypertensive rats, we compared the time course and magnitude of the biochemical effects of angiotensin converting enzyme inhibition on the plasma renin-angiotensin system, cardiac hypertrophy, renal lesions, and 24-hour blood pressure decrease induced by either intermittent angiotensin converting enzyme inhibition administration (benazepril PO, 10 mg/kg once a day, n=93) or continuous administration (benazeprilat, 3 mg/kg per day via osmotic pumps, n=92). Control rats (n=91) received the drug vehicle intermittently or continuously. Mortality was significantly reduced by both intermittent (n=3/93) and continuous (n=3/92) inhibition compared with controls (n=18/91) (P<.001). Changes in the plasma renin-angiotensin system and blood pressure were parallel. A continuous suppression of the activity of the plasma renin-angiotensin system was associated with a 24-hour decrease in blood pressure with continuous inhibition, whereas intermittent inhibition induced a similar fall in blood pressure only for the first hours after gavage. Heart weight (5.12 +/- 0.12, 3.98 +/- 0.09, 4.32 +/- 0.12 g/kg in controls [n=8], continuous inhibition [n=18], and intermittent inhibition [n=18], respectively) was significantly reduced to the same extent by both treatments (P<.0001), and clipped kidney weight (3.28 +/- 0.11, 1.83 +/- 0.12, 2.20 +/- 0.15 g/kg in controls [n=8], continuous inhibition [n=18], and intermittent inhibition [n=18], respectively) was significantly reduced in both groups of treated rats (P<.0001). After removal of the unclipped kidney, plasma creatinine was significantly increased in both treatment groups (P<.0001) compared with nephrectomized hypertensive control rats but to a significantly greater extent in the continuously inhibited rats (117 +/- 39, 317 +/- 8, 260 +/- 8 mumol/L in controls [n=8], continuous inhibition [n=18], and intermittent inhibition [n=18]; P<.0001). Therefore, changes in blood pressure and the plasma renin-angiotensin system were parallel after either continuous or intermittent inhibition. It was possible to decrease blood pressure continuously during 24 hours only with continuous inhibition. Both treatments reduced heart weight to a similar extent. Damage to the clipped kidney, as revealed by elevated plasma creatinine levels after nephrectomy of the unclipped kidney, was slightly reduced but not avoided by the intermittent inhibition.