BACKGROUND Osmotic and neural factors stimulate neuroendocrine activity during exercise. In contrast to excitatory mechanisms, afferent information from cardiac mechanoreceptors inhibits integrative centers in the hypothalamus and medula oblongata, which serves to buffer neuroendocrine activity. Orthotopic cardiac transplantation results in the loss of afferent information from cardiac mechanoreceptors. Thus, transplantation possibly results in exaggerated neuroendocrine responses when patients are physically active. RESULTS We measured the neuroendocrine response to moderate and strenuous exercise performed at the same relative intensity in 11 heart transplant recipients (50 +/- 14 years old) 18 +/- 12 months after transplantation and 11 control subjects matched with respect to sex, age, and body size. Plasma levels of norepinephrine, vasopressin, renin activity, atrial natriuretic peptide, angiotensin II, and aldosterone were measured at rest, during a maximal graded exercise test, and during submaximal exercise at 40% and 70% of peak power output on a cycle ergometer (W). Plasma renin activity and atrial natriuretic peptide were elevated at rest in heart transplant recipients (p < or = 0.05). Heart rate (%HRmax reserve), rating of perceived exertion, and reductions in plasma volume (% delta from rest) at the conclusion of the three exercise conditions did not differ between heart transplant recipients and control (p > or = 0.05). Relative changes in neuroendocrine hormones were similar (p > or = 0.05) in heart transplant recipients and control during exercise at 40% of peak power output. Relative changes in plasma norepinephrine, vasopressin, atrial natriuretic peptide, and plasma renin activity were greater (p < or = 0.05) in heart transplant recipients during exercise at 70% of peak power output and the graded exercise test. CONCLUSIONS We interpret these data as a possible indication of ablation of cardiac mechanoreceptor afferents and unopposed neuroendocrine stimulation in heart transplant recipients. Furthermore, chronic neuroendocrine hyperactivity is likely in ambulatory heart transplant recipients. Although cyclosporine nephrotoxicity is implicated in the development of hypertension, our data suggest that chronic neuroendocrine hyperactivity, which alters renal volume regulation, also contributes to the incidence and severity of hypertension in heart transplant recipients.