EFFECT OF INTENSE ANGIOTENSIN-II SUPPRESSION ON THE DIURETIC RESPONSE TO FUROSEMIDE DURING CHRONIC ACE-INHIBITION

Background Contrary to expectation, most studies have demonstrated that initiation of an angiotensin-converting enzyme (ACE) inhibitor in conventional doses in patients with heart failure reduces the diuretic efficacy of furosemide. Recently, it has been suggested that single low doses (1 mg) but not high doses (25 mg) of captopril enhance furosemide-induced diuresis. It is not known whether the interaction between diuretics and ACE inhibitors are altered during long-term dosing. Methods and Results Eight patients with heart failure treated with diuretics and ACE inhibitors for at least 3 months were studied. Ah patients were established on captopril 12.5 mg three times daily for 2 weeks before the study. Sodium intake was fixed before the study, and usual medication was withheld on study days. Intravenous furosemide was given on each of 2 study days to maintain a moderate, constant diuresis. Renal plasma flow and glomerular filtration rate (GFR) were determined using clearance techniques, and urine was collected hourly over 4 hours. Captopril 12.5 mg or placebo was given in a randomized, single-blind fashion at the end of the first hour. Compared with placebo, captopril reduced plasma concentrations of angiotensin II (23+/-18 versus 4+/-3 pg/mL 1 hour after dosing, P<.02) and systolic (131+/-31 versus 122+/-29 mm Hg, P<.01) and diastolic (74+/-15 versus 67+/-13 mm Hg, P<.05) blood pressures. GFR fell (55+/-24 versus 51+/-22 mL/min, P<.02) and effective renal plasma flow rose during the first (198+/-76 versus 231+/-49 mL/min) and second hours after dosing (185+/-69 versus 247+/-74 mL/min, P<.02). Similarly, urine volumes, in response to furosemide, increased after captopril (238+/-90 versus 283+/-111 mL, P<.05, and 245+/-78 versus 311+/-92 mL, P<.01, 1 and 2 hours after dosing). Urinary electrolyte concentrations fell, but total urinary sodium (22+/-7 versus 28+/-12 mmol/hr, P<.01) and chloride (20+/-6 versus 25+/-11 mmol/hr, P<.05) excretion increased in the 2 hours after dosing, as did fractional excretion of sodium (urinary sodium/urinary creatinine) (61+/-27 versus 75+/-36 mmol/mu mol, P<.01). Conclusions Intense although transient ACE inhibition with captopril enhances the diuretic effects of furosemide during long-term ACE inhibition.