Plasma levels of adrenomedullin are increased in chronic renal failure. The significance of this finding is uncertain, because the biological effects of adrenomedullin in renal impairment are unknown. Therefore, we studied the effects of adrenomedullin infusion in subjects with chronic renal impairment. Eight males with IgA nephropathy and plasma creatinine of 0.19+/-0.03 mmol/L (mean+/-SEM) were studied in a vehicle-controlled crossover design. Each subject was studied twice; subjects were administered either adrenomedullin at a low dose and then a high dose (2.9 and 5.8 pmol/kg per minute, respectively, for 2 hours each) or a 4-hour vehicle control (Hemaccel), in random order, on day 4 of controlled metabolic diets. Adrenomedullin infusion achieved plasma adrenomedullin concentrations in the pathophysiological range after the low (31.2+/-5.1 pmol/L) and high (47.4+/-4.3 pmol/L) dose, and plasma cAMP was increased. Compared with vehicle control, high-dose adrenomedullin increased peak heart rate (+21.7+/-3.3 bpm, P<0.01) and cardiac output (+2.9+/-0.2 L/min, P<0.01) and lowered both systolic and diastolic blood pressures by >10 mm Hg (P<0.05). Plasma renin activity, angiotensin II, and norepinephrine increased by up to 50% above baseline levels (P<0.05 for all), whereas aldosterone and epinephrine were unchanged. Urinary volume and sodium excretion increased significantly (P<0.05) with low-dose adrenomedullin, whereas creatinine clearance was stable, and proteinuria tended to decrease. In subjects with chronic renal impairment due to IgA nephropathy, adrenomedullin infusion lowered blood pressure, stimulated sympathetic activity and renin release, and caused diuresis and natriuresis. Adrenomedullin may have a role in modulating blood pressure and kidney function in renal disease.