Effect of exercise training on endothelium-derived nitric oxide function in humans

Abstract

Vascular endothelial function is essential for maintenance of health of the vessel wall and for vasomotor control in both conduit and resistance vessels. These functions are due to the production of numerous autacoids, of which nitric oxide (NO) has been the most widely studied. Exercise training has been shown, in many animal and human studies, to augment endothelial, NO-dependent vasodilatation in both large and small vessels. The extent of the improvement in humans depends upon the muscle mass subjected to training; with forearm exercise, changes are restricted to the forearm vessels while lower body training can induce generalized benefit. Increased NO bioactivity with exercise training has been readily and consistently demonstrated in subjects with cardiovascular disease and risk factors, in whom antecedent endothelial dysfunction exists. These conditions may all be associated with increased oxygen free radicals which impact on NO synthase activity and with which NO reacts; repeated exercise and shear stress stimulation of NO bioactivity redresses this radical imbalance, hence leading to greater potential for autacoid bioavailability. Recent human studies also indicate that exercise training may improve endothelial function by up-regulating eNOS protein expression and phosphorylation. While improvement in NO vasodilator function has been less frequently found in healthy subjects, a higher level of training may lead to improvement. Regarding time course, studies indicate that short-term training increases NO bioactivity, which acts to homeostatically regulate the shear stress associated with exercise. Whilst the increase in NO bioactivity dissipates within weeks of training cessation, studies also indicate that if exercise is maintained, the short-term functional adaptation is succeeded by NO-dependent structural changes, leading to arterial remodelling and structural normalization of shear. Given the strong prognostic links between vascular structure, function and cardiovascular events, the implications of these findings are obvious, yet many unanswered questions remain, not only concerning the mechanisms responsible for NO bioactivity, the nature of the cellular effect and relevance of other autacoids, but also such practical questions as the optimal intensity, modality and volume of exercise training required in different populations.

Figures

Figure 1. Effect of localized handgrip (left panels) and cycle ergometer (right panels) exercise on brachial artery haemodynamics

Mean blood flow (A), antegrade (B) and retrograde (C) flows during exercise under saline (S; light bars) and l-NMMA (L; dark bars) infusion are displayed. l-NMMA significantly decreased flows under the cycle condition only (2-way ANOVA). Note that, although mean flows are lower during cycle exercise, the magnitude of antegrade flows are similar to handgrip exercise and there is substantial retrograde flow during cycling which is not evident during handgrip. This systolic antegrade, diastolic retrograde flow pattern and its accompanying oscillatory shear stress on the endothelium may explain the paradoxical greater contribution of NO during cycling than handgrip exercise, despite the greater mean flow during handgrip exercise. This difference in flow patterns may also resolve another conundrum in the literature, that exercise training studies involving localized handgrip training have not always produced significant improvement in NO bioactivity (Green et al. 1994, 1996a; Franke et al. 1998), whilst studies which have utilized typical ‘whole body’ exercise training regimes, predominantly involving lower limb exercise (cycling, running, etc.), have observed improvements in NO-mediated vasodilator capacity, even in the untrained upper limbs (Kingwell et al. 1997b; Maiorana et al. 2000, 2001a; Linke et al. 2001; Walsh et al. 2003a,b). An acute bout of cycle exercise may be a more potent stimulus to endothelial NO production in the forearm vasculature than a bout of localized handgrip exercise. (Green et al. in press).

Figure 2. Hypothesized response of arteries to increased flow and shear stress following varying durations of exercise training

In the untrained vessel (left panel), basal release of NO causes subjacent smooth muscle cell vasodilatation which acts to homeostatically regulate wall shear. In response to medium-term exercise training (middle panel), acute increase in shear stress, associated with repetitive exposure to increased flow during bouts of exercise, stimulates increased endothelial NO production and consequent vasodilatation. Up-regulation of the NO-dilator system, including eNOS expression, occurs to buffer increased shear stress. Following long-term exercise training (right panel), structural adaptation occurs, possibly in part due to NO-mediated remodelling, resulting in chronic increase in vessel calibre which ‘structurally normalises’ shear stress. NO function returns towards baseline levels. Figure based on Maiorana et al. (2003). Permission granted by Adis International Ltd.

Figure 3. Reactive hyperaemic forearm blood flow (A) and change in forearm blood flow response to three doses of acetylcholine (ACh; B) in the preferred (▪) and non-preferred (□) forearms of elite single-handed tennis players (*P < 0.05) (Green et al. 1996a)

Peak reactive hyperaemia provides an index of resistance vessel structure and the higher preferred limb data indicates that chronic or recurrent episodic changes in blood flow induce arterial remodelling in humans which enhances vasodilator capacity. Responses to ACh, which provide an index of stimulated endothelium-dependent activity, did not differ between the limbs, indicating that chronic training is not associated with altered endothelium-dependent vascular responses. This study supports the schema presented in Fig. 2, that NO production and bioactivity initially produce a short-term buffer to the increased shear associated with exercise. Following extended training, arterial remodelling results in an increase in lumen diameter (Brown, 2003; Prior et al. 2003) which ‘structurally’ normalizes shear and endothelial NO activity returns towards initial levels. Figure based on Green et al. (1996a). Permission granted by the American Physiological Society.