We investigated the relationship between exercise capacity and the level of neurohormonal activation at rest and during exercise in patients with various degrees of severity of chronic heart failure. We performed exercise testing with measurements of peak oxygen consumption (pVo2) and blood sampling at rest and at peak exercise in eight patients with moderate heart failure (pVo2 = 17 +/- 0.4 ml/kg/min) (mean +/- S.E.M.) and eight patients with severe CHF (pVo2 = 9 +/- 1 ml/kg/min). None of the patients was taking angiotensin converting enzyme inhibitors or beta-blockers. Plasma levels of atrial natriuretic peptide, cGMP, arginine-vasopressin, renin, angiotensin II, epinephrine and norepinephrine increased significantly (P < 0.01), from rest to peak exercise, in all patients. Among all the studied neurohormonal factors, only atrial natriuretic peptide levels at rest as well as at peak exercise, in patients with severe heart failure were correlated significantly to pVo2 (r = -0.77, P = 0.04; r = -0.85, P = 0.01, respectively) and to exercise duration (r = -0.72, P = 0.05; r = -0.79; P = 0.03, respectively). The relationship between plasma levels of atrial natriuretic peptide and of cGMP was shifted downward in the more severe patients suggesting the loss of biological activity of atrial natriuretic peptide.