To investigate whether cardiac innervation modulates atrial natriuretic peptide (ANP) secretion, we performed acute volume expansion on eight normal and eight matched (age, weight, and total blood volume) transplanted denervated heart patients (Htx), while monitoring fluid-regulating hormone, systemic blood pressure, and echocardiographic atrial area changes. At rest, plasma ANP and guanosine 3',5'-cyclic monophosphate (cGMP) were lower in control subjects than in Htx (45 +/- 16 vs. 103 +/- 35 pg/l and 0.9 +/- 0.3 vs. 3.5 +/- 1.4 pM, respectively; P < 0.001). Plasma active renin, aldosterone, and catecholamines did not differ significantly in the two populations, whereas arginine vasopressin and cortisol were higher in controls (P < 0.01 and P < 0.005). Although volume expansion (+15%) and atrial stretch were similar in the two groups, plasma ANP and cGMP increased significantly only in the Htx group (103 +/- 35 to 189 +/- 69 pg/l and 3.5 +/- 1.4 to 5.8 +/- 1.4 pM, respectively; P < 0.001). The decrease observed for the other hormones was not significant except for arginine vasopressin and cortisol (P < 0.05 and P < 0.001) in the control group. These results support the hypothesis of an inhibitory role of cardiac innervation in biologically active ANP secretion in humans, at rest and after acute volume expansion.