Endogenous nitric oxide in the control of skeletal muscle oxygen extraction during exercise

Abstract

Our previous studies uncovered an inhibitory effect of nitric oxide (NO) on leg skeletal muscle respiration in dogs at rest. The role of NO in the modulation of O2 consumption and O2 extraction in hindlimb muscle during elevated metabolic states was investigated in chronically instrumented dogs while walking and at three exercise intensities which markedly increased hindlimb blood flow. Walking resulted in increased O2 consumption by 17 +/- 4 mL min-1 and O2 extraction from 24 +/- 1 to 37 +/- 8%, with no alteration in hindlimb blood flow (BFLeg) and vascular resistance (VRLeg). Running at the highest speed (9.1 mph) resulted in an increase in BFLeg from 0.67 +/- 0.05 to 2.2 +/- 0.1 L min-1, a reduction of VRLeg and elevation of hindlimb O2 consumption from 33 +/- 3 to 226 +/- 21 mL min-1 and O2 extraction from 29 +/- 2 to 61 +/- 5%, with a decrease in leg venous PO2 from 38 +/- 1 to 25 +/- 1 mmHg. After nitro-L-arginine (NLA) (35 mg kg-1, i.v.) to inhibit endogenous NO synthesis, walking caused greater increases in hindlimb O2 consumption (29 +/- 5 mL min-1) and O2 extraction (43 +/- 1 to 60 +/- 3%) (both P < 0.05), with no significant change in BFLeg. During running at the highest speed, BFLeg was 1.9 +/- 0.1 L min-1 (P < 0. 05) and VRLeg was higher, accompanied by increases in hindlimb O2 consumption from 49 +/- 7 to 318 +/- 24 mL min-1 and O2 extraction from 41 +/- 2 to 79 +/- 4% (both P < 0.05), with a greater decrease in leg venous PO2 from 33 +/- 1 to 20 +/- 1 mmHg (P < 0.05). Similar results were found for intermediate levels of exercise. Our results indicate that NO modulates hindlimb skeletal muscle O2 extraction and O2 usage whether blood flow increased or not during exercise.

Opposing effects of nitric oxide and prostaglandin inhibition on muscle mitochondrial V̇o2 during exercise

“…These findings have been interpreted as an O 2 delivery limitation owing to reduced muscle blood flow. Consistent with this interpretation, there are reports of no effect (1,4) or an increase (35) in muscle V O 2 during "submaximal" exercise in animals where increased O 2 extraction compensates for a lower blood flow. In humans, NOS inhibition alone has no effect on V O 2 across the exercising leg, but when combined with PG synthesis, inhibition by indomethacin, a significant reduction in blood flow is compensated for by varying levels of O 2 extraction (14,15,28,33).…”

“…In animals, NOS inhibition has been shown to lower muscle V O 2 during evoked contractions (2,20,22,30,31,41), while other studies show no effect (1,4) or an increase (35) in muscle V O 2 during voluntary exercise. In humans, NOS inhibition alone has been found to have little or no effect on V O 2 across the exercising leg or forearm measured by the Fick method (15,28,33).…”

Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition

“…This is in accordance with in vitro studies which suggest that NO competes with oxygen and tonically inhibits mitochondrial respiration by binding to the cytochrome c oxidase complex (3,4,8,9,22). Some animal studies have also previously found increased V O 2 when NO formation is blocked (33)(34)(35). Previous studies that have blocked NOS in humans by infusion of either L-NAME or L-NMMA (10,27) have shown a similar lowering of resting blood flow as in the current study but no effect on oxygen uptake.…”

“…By use of in vitro preparations, it has been demonstrated that the primary effect of exogenous NO on mitochondrial activity is a reversible and competitive inhibition of cytochrome oxidase activity (5,6,32). Some animal studies have subsequently found evidence that NO tonically inhibits mitochondrial respiration in vivo (33)(34)(35), but there has not been evidence for this in humans (10,27,31). It is well shown with various methods that prostanoids can act synergistically with NO to regulate vascular function in health and disease (2,19,23,30,31), but COX inhibition may also have direct effects on cellular aerobic respiration by affecting uncoupling (17,20,23).…”

Limited Exercise Capacity in Heterozygous Manganese Superoxide Dismutase Gene–Knockout Mice

“…4 -6 We have shown that NO plays an important role in the modulation of oxygen consumption (V O 2 ) and oxygen extraction in hindlimb skeletal muscle at elevated metabolic states during walking or running whether or not blood flow increases. 7 Given that the balance between oxygen utilization and oxygen supply is a major factor responsible for the ability to maintain long-term exercise and support maximal exercise performance, 8 a loss of NO production might lead to decreased exercise capacity by increasing V O 2 . More recently, we have shown that there is a limitation of exercise capacity in male mice with defects in the expression of endothelial NO synthase (eNOS), which is associated with a greater increase in whole-body V O 2 than in wild-type mice.…”