CANINE HINDLIMB BLOOD-FLOW AND O-2 UPTAKE AFTER INHIBITION OF EDRF/NO SYNTHESIS

The nitric oxide synthase (NOS) inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME) was used to determine whether the decrease in canine hindlimb blood flow (Q(L)) with NOS inhibition would limit skeletal muscle O-2 uptake (Vo(2)). Arterial inflow and venous outflow from the hindlimb were isolated, and the paw was excluded from the circulation. Pump perfusion from the right femoral artery kept the hindlimb perfusion pressure near the autoperfused level. Six anesthetized dogs received L-NAME (20 mg/kg iv), whereas another group of five dogs received the stereospecific enantiomer N omega-nitro-D-arginine methyl ester (D-NAME, 20 mg/kg iv). Efficacy of NOS inhibition was tested with intra-arterial boluses of acetylcholine. Q(L) was measured continuously, and whole body and hindlimb Vo(2) were measured 60 and 120 min after L-NAME or D-NAME. Whole body iio, remained at control levels, but cardiac output decreased from 117 +/- 17 to 57 +/- 7 ml.kg(-1).min(-1) 60 min after L-NAME (P < 0.05) and remained at that level for the duration of the experiment. Cardiac output was significantly higher in the D-NAME group than in the L-NAME group at 60 min. After L-NAME, Q(L) fell 24% but Vo(2) increased from 5.2 +/- 0.4 to 7.4 +/- 0.6 ml.kg(-1).min(-1) (P < 0.05). No change in Q(L) or Vo(2) occurred after D-NAME. NOS inhibition did not limit hindlimb Vo(2), despite decreases in blood flow. The surprising increase in hindlimb Vo(2) suggests that the role of endothelium-derived relaxing factor/NO in the regulation of skeletal muscle blood flow must now be considered in conjunction with its associated effects on O-2 demand.