BACKGROUND: Limitation of the blood supply to skeletal muscle in chronic heart failure may contribute to the symptoms of fatigue and diminished exercise capacity. The pathophysiology underlying this abnormality is not known. The purpose of this study was to assess the effect of endothelium dependent and independent vasodilator agents on blood flow in the leg of patients with heart failure. METHODS AND RESULTS: Blood flow in the leg was measured in patients with heart failure (n = 20) and compared with that in patients with ischaemic heart disease and normal left ventricular function (n = 16) and patients with chest pain and normal coronary arteries (n = 8). External iliac artery blood flow was measured using intravascular Doppler ultrasound and quantitative angiography. Flow was recorded at rest and in response to bolus doses of the endothelium independent vasodilator, papaverine. Endothelium dependent responses were measured by infusion of acetylcholine and substance P. Mean (SEM) baseline blood flow was reduced at rest (2.9 (0.4) v 4.5 (0.3) ml/s, P < 0.001) and vascular resistance was raised (37.4 (3.6) v 27.1 (3.0) units, P < 0.05) in patients with heart failure compared with that in controls. The peak blood flow response to papaverine (8 mg), acetylcholine (10(-7)-10(-5) mol/l), and substance P (5 pmol/min) was reduced in heart failure, with greater impairment of the response to acetylcholine than substance P. There was a correlation between baseline blood flow in the heart failure group and diuretic dose (r = -0.62, P = 0.003), New York Heart Association classification (r = -0.65, P = 0.002), and left ventricular ejection fraction (r = 0.80, P = 0.0004). CONCLUSIONS: There is reduced blood flow and raised vascular resistance at rest in the legs of patients with heart failure. The degree of impaired blood flow in the leg correlates with the severity of heart failure. There is impairment of the response to both endothelium dependent and independent vasodilators. Abnormal function of the vascular myocyte in heart failure may explain these results as would structural abnormalities of the resistance vessels.