Local control of skeletal muscle blood flow during exercise: influence of available oxygen

Abstract

Reductions in oxygen availability (O(2)) by either reduced arterial O(2) content or reduced perfusion pressure can have profound influences on the circulation, including vasodilation in skeletal muscle vascular beds. The purpose of this review is to put into context the present evidence regarding mechanisms responsible for the local control of blood flow during acute systemic hypoxia and/or local hypoperfusion in contracting muscle. The combination of submaximal exercise and hypoxia produces a "compensatory" vasodilation and augmented blood flow in contracting muscles relative to the same level of exercise under normoxic conditions. A similar compensatory vasodilation is observed in response to local reductions in oxygen availability (i.e., hypoperfusion) during normoxic exercise. Available evidence suggests that nitric oxide (NO) contributes to the compensatory dilator response under each of these conditions, whereas adenosine appears to only play a role during hypoperfusion. During systemic hypoxia the NO-mediated component of the compensatory vasodilation is regulated through a β-adrenergic receptor mechanism at low-intensity exercise, while an additional (not yet identified) source of NO is likely to be engaged as exercise intensity increases during hypoxia. Potential candidates for stimulating and/or interacting with NO at higher exercise intensities include prostaglandins and/or ATP. Conversely, prostaglandins do not appear to play a role in the compensatory vasodilation during exercise with hypoperfusion. Taken together, the data for both hypoxia and hypoperfusion suggest NO is important in the compensatory vasodilation seen when oxygen availability is limited. This is important from a basic biological perspective and also has pathophysiological implications for diseases associated with either hypoxia or hypoperfusion.

Fig. 1.

Thigh plasma venous ATP responses at rest and during incremental knee-extensor exercise with exposure to normoxia, hypoxia, hyperoxia, and carbon monoxide (CO) + normoxia. *Significantly different from resting values (P < 0.05). [Adapted with permission from Ref. 48].

Fig. 2.

Effects of CO on the rise of systemic arterial pressure to graded reductions in hindlimb perfusion during exercise (2 mph, 0% grade). Squares and solid lines are control (no CO) exercise data, and circles and dashed lines are exercise with CO data. Filled symbols represent free-flow data; open symbols represent data collected during reduced hindlimb perfusion. These data demonstrate that when terminal aortic flow is decreased during mild exercise the reflex rise in systemic arterial pressure occurs at higher flows after arterial oxygen content is reduced with CO. [Adapted with permission from Ref. 139].

Fig. 3.

Schematic of intra-arterial balloon catheter system. Forearm blood flow is reduced by partially occluding the brachial artery via inflation of a Fogarty balloon catheter with saline using a calibrated microsyringe for tight control of balloon volume. Brachial artery blood velocity is measured (via Doppler ultrasound) proximal to the balloon. The configuration of the balloon upstream from the lumen of the introducer allows measurement of the brachial arterial pressure (BAP) distal to the balloon that is perfusing the contracting forearm muscles. Rhythmic forearm exercise is performed with a hand grip device by lifting a weight 4–5 cm over a pulley system at a duty cycle of 1 s contraction/ and 2-s relaxation (20 contractions/min).

Fig. 4.

Linear regression analysis of the relationship between % recovery of forearm blood flow (FBF) and reduction in vascular resistance (%) during balloon inflation (n = 151) from all trials performed in references (–23). The correlation demonstrates that the magnitude of flow restoration is predicted by the reduction in vascular resistance during forearm exercise with hypoperfusion.

Fig. 5.

Reduction in compensatory vasodilation [i.e., % recovery of forearm vascular conductance (FVC) compared with respective control (no drug) trial] during various pharmacological trials. Single inhibition of NOS with N^G-monomethyl-l-arginine (white bar) and adenosine receptor blockade with aminophylline (black bar) substantially attenuates the compensatory vasodilation during exercise with acute hypoperfusion. Combined NOS/ADO inhibition (dark gray bar) reveals an even greater reduction in %FVC compared with blockade of each factor alone. Single inhibition of COX with Ketorolac has minimal effect on the compensatory vasodilation (light gray bar). Combined NOS/COX inhibition (hatched bar) has minimal effect on the compensatory vasodilation compared with NOS inhibition alone (white bar). Data were derived from Refs. –. ADO, adenosine; COX, cyclooxygenase; NOS, nitric oxide synthase; PG, prostaglandin.