Having it both ways? Vasoconstriction in contracting muscles

For nearly 100 years one major focus of The Journal of Physiology has been the integrated physiological responses to exercise (Krogh & Lindhard, 1913). A key element of this response is the redistribution of cardiac output to the active muscles. This is accomplished in part by activation of the sympathetic nervous system, which causes vasoconstriction in visceral organs and inactive muscles thereby redirecting blood flow to the active muscles. However, a major unresolved question is what effect this sympathetic outflow has on the vasculature in the active muscles. One idea is that the vasodilating substances associated with contraction promote a ‘functional sympatholysis’ that limits the ability of the sympathetic nerves to cause vasoconstriction in the active muscles (Remensnyder et al. 1962). This scheme is attractive because it insures tight linkage between the metabolic demands of the contracting muscles and blood flow. It is also attractive because only ‘inactive tissues’ are subject to robust vasoconstriction when sympathetic outflow increases with exercise thus directing a large fraction of total cardiac output to the contracting muscles. In recent studies published in The Journal of Physiology, functional sympatholysis has been clearly shown in humans and animals, although the underlying mechanisms may differ depending on the species (Thomas & Victor, 1998; Hansen et al. 2000; Ruble et al. 2002; Tschakovsky et al. 2002; Rosenmeier et al. 2003).

However, in spite of the ideas and evidence touched on above, functional sympatholysis could present a problem in the setting of whole body dynamic exercise. For example, muscle blood flow in both humans and animals can be very high (Andersen & Saltin, 1985). If sympatholysis was absolute (i.e. sympathetic constriction was abolished in active muscle) and a large mass of muscle was dilated, systemic blood pressure might fall during exercise. This is exactly what happens when patients with conditions that limit sympathetic outflow to their active muscles engage in even mild whole body exercise (Marshall et al. 1961). So, the question becomes, can you have it both ways? Is it possible to both ‘protect’ blood flow to the active muscles and regulate arterial pressure at the same time? In this issue of The Journal of Physiology, Van Teeffelen & Segal (2003) provide insight into a regulatory scheme that might operate ‘both ways’. The main finding of their study, conducted in the microcirculation of contracting hamster muscles, is that when the muscle contracts there is marked sympatholysis in the smallest arterioles perfusing the muscle, but that sympathetic constriction in the upstream feed arteries and first-order arterioles is largely preserved. Additionally, this pattern of altered constrictor responses (especially in the smallest arterioles) is specific for muscle contraction because it does not occur during passive drug-induced vasodilatation.

Why are these findings important? First, they are entirely consistent with pharmacological data from rodent muscle showing that sympathetic vasoconstriction is mediated predominantly by α₁ adrenergic receptors in the larger arterioles and by α₂ adrenergic receptors in the smaller arterioles (Anderson & Faber, 1991). Additionally, α₂ adrenergic vasoconstriction appears to be especially sensitive to ‘metabolic’ inhibition by substances likely to be released from contracting muscles. Therefore, the loss of vasoconstrictor responsiveness during exercise in the smallest vessels studied by Van Teeffelen & Segal (2003) demonstrates a functional significance to these important pharmacological ideas. Second, with exercise the main site of vascular resistance is likely to move ‘upstream’ to larger calibre vessels. The observations by VanTeeffelen & Segal mean that these vessels could then still actively participate in the regulation of arterial blood pressure.

This second idea is also consistent with other important concepts concerning how blood pressure is regulated during whole body exercise in the face of marked vasodilatation in the contracting muscles. When most of the cardiac output is directed to one vascular bed (i.e. muscle during exercise) a modest vasoconstrictor response in the dilated vascular bed will have a profound effect on blood pressure. By contrast when only a small fraction of the total cardiac output is going to muscle (i.e. rest) it must undergo marked constriction for there to be much effect on blood pressure (O'Leary, 1991). Additionally, even though preserved constrictor responses in the feed arteries and first-order arterioles might permit regulation of total blood flow to the active muscles, sympatholysis in the second- and third-order arterioles would insure that the blood flow available would be distributed to the most metabolically ‘stressed’ areas of the active muscles. Together the data from VanTeeffelen and Segal provide great insight into how the sympathetic nerves might ‘control’ total muscle blood flow to regulate arterial pressure during whole body exercise, while at the same time preferentially directing the available flow to the most metabolically active muscle fibres. In this way, arterial blood pressure can still be regulated and oxygen delivery to the active muscles distributed in an efficient way.

In summary, Van Teeffelen & Segal (2003) have provided essential data that let those interested in the sympathetic neural control of the peripheral circulation during exercise have it ‘both ways’.