Inhibition of nitric oxide and prostaglandins, but not endothelial-derived hyperpolarizing factors, reduces blood flow and aerobic energy turnover in the exercising human leg

Prostaglandins, nitric oxide (NO) and endothelial-derived hyperpolarizing factors (EDHFs) are substances that have been proposed to be involved in the regulation of skeletal muscle blood flow during physical activity. We measured haemodynamics, plasma ATP and V-O2 at rest and during one-legged knee-extensor exercise (19 +/- 1 W) in nine healthy subjects with and without intra-arterial infusion of indomethacin (Indo; 621 +/- 17 mu g min(-1)), Indo + N-G-monomethyl-L-arginine (L-NMMA; 12.4 +/- 0.3 mg min(-1)) (double blockade) and Indo + L-NMMA + tetraethylammonium chloride (TEA; 12.4 +/- 0.3 mg min(-1)) (triple blockade). Double and triple blockade lowered leg blood flow (LBF) at rest (P < 0.05), while it remained unchanged with Indo. During exercise, LBF and vascular conductance were 2.54 +/- 0.10 l min(-1) and 25 +/- 1 mmHg, respectively, in control and they were lower with double (33 +/- 3 and 36 +/- 4%, respectively) and triple (26 +/- 4 and 28 +/- 3%, respectively) blockade (P < 0.05), while there was no difference with Indo. The lower LBF and vascular conductance with double and triple blockade occurred in parallel with a lower O-2 delivery, cardiac output, heart rate and plasma [noradrenaline] (P < 0.05), while blood pressure remained unchanged and O-2 extraction and femoral venous plasma [ATP] increased. Despite the increased O-2 extraction, leg V-O2 was 13 and 17% (triple and double blockade, respectively) lower than control in parallel to a lower femoral venous temperature and lactate release (P < 0.05). These results suggest that NO and prostaglandins play important roles in skeletal muscle blood flow regulation during moderate intensity exercise and that EDHFs do not compensate for the impaired formation of NO and prostaglandins. Moreover, inhibition of NO and prostaglandin formation is associated with a lower aerobic energy turnover and increased concentration of vasoactive ATP in plasma.