RENAL EFFECTS OF ACE INHIBITION IN OVINE HEART-FAILURE - A COMPARISON OF INTERMITTENT AND CONTINUOUS ACE INHIBITION

Results of uncontrolled studies suggest that the duration of action of an ACE inhibitor may be an important determinant of renal impairment when using these agents to treat patients with heart failure. To determine whether there is experimental evidence for this hypothesis, we compared the effects of intermittent (captopril, 25 mg i.v. bolus twice daily) and continuous (captopril, 25 mg bolus, then 50 mg/day by constant infusion) ACE inhibition in an ovine model where heart failure was induced by rapid left ventricular pacing (LVP). Six sheep underwent three 4-day periods of LVP with intermittent, continuous, or no treatment (control) given in random order from the onset of LVP. Despite evidence that intermittent captopril administration allowed significant recovery of serum ACE activity (4.6 ± 1.2 vs. 1.1 ± 0.5 pmol/L before and after captopril bolus on day 4, p < 0.001) and restitution of arterial pressure between successive boluses (48 ± 7 vs. 41 ± 4 mm Hg, p < 0.01), there was no difference in the renal effects of intermittent and continuous ACE inhibition (creatinine clearance was 44 ± 14 and 47 ± 8 ml/min on day 4 of the intermittent and continuous phase, respectively). Nevertheless, there was a significant correlation between the decline in arterial pressure and fall in creatinine clearance induced by ACE inhibition (r = 0.65, p < 0.05), with evidence that drug accumulation may potentiate hypotension and renal impairment should arterial pressure be reduced below the threshold for renal autoregulation. Thus, under the experimental conditions of this study, the duration of action of ACE inhibition per se does not appear to be a major determinant of renal impairment in heart failure that largely results from hypotension and reduced renal perfusion. © 1990 Raven Press, Ltd., New York.