1. Adrenomedullin (ADM) is a recently characterized circulating hormone which affects haemodynamic, renal and pituitary function in mammals. We have shown previously that in sheep, ADM produces vasodilatation together with increases in cardiac output and contractility. However, whether these effects are direct or mediated by autonomic reflexes is unclear. The present study examined the cardiovascular actions of an intravenous infusion of ADM in conscious, chronically instrumented sheep with either sympathetic, parasympathetic or autonomic ganglion blockade, to determine the role of the autonomic nervous system in mediating these cardiovascular changes. 2. Human ADM (1-52) was infused for 60 min at 2 micrograms kg-1 h-1 following: (1) saline control, (2) combined alpha/beta-adrenoceptor (sympathetic) blockade (proporanolol 0.4 mg kg-1 h-1 + phentolamine 0.15 mg kg-1 h-1 for 20 h), (3) muscarinic (parasympathetic) blockade (methscopolamine 0.05 mg kg-1 h-1 for 20 h) or (4) ganglion blockade (hexamethonium 3 mg kg-1 h-1 for 4 h). Measurements were made of mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral conductance (TPC), maximal aortic flow (Fmax) and maximal rate of change of aortic flow (dF/dt). 3. ADM reduced MAP by 3 +/- 1 mmHg, and increased CO (1.2 +/- 0.2 l min-1), HR (14 +/- 2 beats min-1), TPC (21 +/- 3 ml min-1 mmHg-1). Fmax (2.3 +/- 0.8 l min-1) and dF/dt (86 +/- 21 l min-1 s-1) in normal sheep. In animals with alpha/beta blockade, similar changes were observed with ADM. However, during muscarinic blockade, the increases in HR (32 +/- 4 beats min-1), CO (2.1 +/- 0.4 l min-1), TPC (31 +/- 4 ml min-1 mmHg-1). Fmax (4.0 +/- 0.6 l min-1), and dF/dt (150 +/- 12 l min-1 s-1) produced by ADM were enhanced. During ganglion blockade, ADM produced a greater reduction in MAP (-10 +/- 2 mmHg) compared to controls (-3 +/- 1 mmHg). However, there was no increase in HR. The changes in CO, TPC and contractility were similar to those observed in control animals. 4. These results suggest that the vasodilator effects of ADM on the periphery and its ability to increase CO and cardiac contractility are not mediated by the autonomic nervous system, but are probably the result of direct actions of ADM on the heart and vasculature.