Inhibition of Nitric Oxide Synthase by L‐NAME Speeds Phase II Pulmonary V̇_O2 Kinetics in the Transition to Moderate‐Intensity Exercise in Man

Abstract

There is evidence that the rate at which oxygen uptake (.VO2) rises at the transition to higher metabolic rates within the moderate exercise intensity domain is modulated by oxidative enzyme inertia, and also that nitric oxide regulates mitochondrial function through competitive inhibition of cytochrome c oxidase in the electron transport chain. We therefore hypothesised that inhibition of nitric oxide synthase (NOS) by nitro-L-arginine methyl ester (L-NAME) would alleviate the inhibition of mitochondrial .VO2 by nitric oxide and result in a speeding of .VO2 kinetics at the onset of moderate-intensity exercise. Seven males performed square-wave transitions from unloaded cycling to a work rate requiring 90 % of predetermined gas exchange threshold with and without prior intravenous infusion of L-NAME (4 mg kg-1 in 50 ml saline over 60 min). Pulmonary gas exchange was measured breath-by-breath and .VO2 kinetics were determined from the averaged response to four exercise bouts performed in each condition using a mono-exponential function following elimination of the phase I response. There were no significant differences between the control and L-NAME conditions for baseline .VO2 (means +/- S.E.M. 797 +/- 32 vs. 794 +/- 29), the duration of phase I (15.4 +/- 0.8 vs. 17.2 +/- 0.6), or the steady-state increment in .VO2 above baseline (1000 +/- 83 vs. 990 +/- 85 ml min-1), respectively. However, the phase II time constant of the .VO2 response was significantly smaller following L-NAME infusion (22.1 +/- 2.4 vs. 17.9 +/- 2.3; P < 0.05). These data indicate that inhibition of NOS by L-NAME results in a significant (19 %) speeding of pulmonary .VO2 kinetics in the transition to moderate-intensity cycle exercise in man. At least part of the intrinsic inertia to oxidative metabolism at the onset of moderate-intensity exercise may result from competitive inhibition of mitochondrial .VO2 by nitric oxide at cytochrome c oxidase, although other mechanisms for the effect of L-NAME on .VO2 kinetics remain to be explored.

Dietary nitrate supplementation reduces the O2cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans

“…This is consistent with our laboratory's previous reports that the p was significantly faster when NOS activity was inhibited by L-NAME (38,39,66). The p was also slightly longer during moderate exercise (group mean p 29 vs. 26 s for BR and PL), but this difference was not statistically significant.…”

“…The inhibition of NO synthesis has previously been shown to increase steady-state V O 2 in dogs (56), but not humans (38) or horses (41). It is widely accepted, however, that NO is involved in the regulation of mitochondrial O 2 consumption.…”

“…Upon the initiation of moderate-intensity exercise [i.e., exercise performed at work rates below the gas exchange threshold (GET)], pulmonary O 2 uptake (V O 2 ), which closely reflects O 2 consumption in the skeletal muscles (2,29,38), rises in an exponential fashion to attain a "steady state" within ϳ2-3 min in healthy humans (64). The steady-state increase in V O 2 is linearly related to the increase in external work rate; is essentially independent of factors such as age, health status or aerobic fitness; and approximates 10 ml O 2 ⅐min Ϫ1 ⅐W Ϫ1 of external power output during cycle ergometry (i.e., 10 ml ⅐min Ϫ1 ⅐W Ϫ1 ; Ref.…”

Biochemical Background of the VO2 On-Kinetics in Skeletal Muscles

“…An administration of β-adrenergic blockade slows down the O 2 on-kinetics in humans [41], whereas an administration of L-NAME, causing an inhibition of nitric oxide synthase, significantly accelerates the O 2 on-kinetics in a thoroughbred horse [42], as well as in humans [43,44]. The authors concluded that the intrinsic inertia of oxidative metabolism at the onset of heavy-intensity exercise may result from an inhibition of mitochondrial respiration by nitric oxide.…”

“…The discussed findings indicate that the rate of oxygen uptake at the onset of exercise may be affected by the interventions contributing to oxygen delivery to the working muscles (especially at high-power output exercise) [37,38,40] and the factors affecting the rate of muscle metabolism [41][42][43][44]16].…”