TY - JOUR

T1 - Opposing effects of nitric oxide and prostaglandin inhibition on muscle mitochondrial VO2 during exercise

AU - Boushel, Robert C

AU - Fuentes, Teresa

AU - Hellsten, Ylva

AU - Saltin, Bengt

N1 - CURIS 2012 5200 035

PY - 2012

Y1 - 2012

N2 - Nitric oxide (NO) and prostaglandins (PG) together play a role in regulation blood flow during exercise. NO also regulates mitochondrial oxygen consumption through competitive binding to cytochrome c oxidase. Indomethacin both uncouples and inhibits the electron transport chain in a concentration-dependent manner, and thus inhibition of NO and PG may regulate both muscle oxygen delivery and utilization. The purpose of this study was to examine the independent and combined effects of NO and PG blockade (L-NMMA and indomethacin respectively) on mitochondrial respiration in human muscle following knee extension (KE) exercise. Mitochondrial respiration was measured ex-vivo by high resolution respirometry in saponin-permeabilized fibers following 6 min KE in control (CON, n=8), arterial infusion of LNMMA (n=4) and Indo (n=4) followed by combined inhibition of NO and PG (L-NMMA + Indo, n=8). ADP-stimulated state 3 respiration with substrates for complex I (glutamate, malate) was reduced 50% by Indo. State 3 O(2) flux with complex I and II substrates was reduced less with both Indo (20%) and L-NMMA + Indo (15%) compared to CON. The results indicate that indomethacin reduces state 3 mitochondrial respiration primarily at complex I of the respiratory chain while blockade of NO by addition of L-NMMA counteracts the inhibition of Indo. This metabolic effect in concert with a reduction of blood flow likely accounts for in-vivo changes in muscle O(2) consumption during combined blockade of NO and PG.

AB - Nitric oxide (NO) and prostaglandins (PG) together play a role in regulation blood flow during exercise. NO also regulates mitochondrial oxygen consumption through competitive binding to cytochrome c oxidase. Indomethacin both uncouples and inhibits the electron transport chain in a concentration-dependent manner, and thus inhibition of NO and PG may regulate both muscle oxygen delivery and utilization. The purpose of this study was to examine the independent and combined effects of NO and PG blockade (L-NMMA and indomethacin respectively) on mitochondrial respiration in human muscle following knee extension (KE) exercise. Mitochondrial respiration was measured ex-vivo by high resolution respirometry in saponin-permeabilized fibers following 6 min KE in control (CON, n=8), arterial infusion of LNMMA (n=4) and Indo (n=4) followed by combined inhibition of NO and PG (L-NMMA + Indo, n=8). ADP-stimulated state 3 respiration with substrates for complex I (glutamate, malate) was reduced 50% by Indo. State 3 O(2) flux with complex I and II substrates was reduced less with both Indo (20%) and L-NMMA + Indo (15%) compared to CON. The results indicate that indomethacin reduces state 3 mitochondrial respiration primarily at complex I of the respiratory chain while blockade of NO by addition of L-NMMA counteracts the inhibition of Indo. This metabolic effect in concert with a reduction of blood flow likely accounts for in-vivo changes in muscle O(2) consumption during combined blockade of NO and PG.

U2 - 10.1152/ajpregu.00044.2012

DO - 10.1152/ajpregu.00044.2012

M3 - Journal article

C2 - 22552792

VL - 303

SP - R94-R100

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6119

IS - 1

ER -