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Training-induced alterations in contractile function and excitation-contraction coupling in vascular smooth muscle


Medicine & Science in Sports & Exercise: January 1998 - Volume 30 - Issue 1 - pp 60-66
Basic Sciences: Brief Review

Aerobic training-induced changes in vascular reactivity have been evaluated in vessels of a variety of sizes and tissue origins. In trained animals large coronary arteries have increased responses to adenosine (Ad) and decreased responses to norepinephrine (NE) and nitroprusside (Np). Smaller coronary arterioles have increased responses to bradykinin (Bk) but not Ad; intermediate size vessels have enhanced responses to both Ad and Bk. A similar size dependence has been found in the vascular bed of the rat spinotrapezius muscle. The terminal feed arteries of trained animals demonstrate increased dilation in response to Np and increased constriction in response to epinephrine (Epi) and NE. Smaller arterioles demonstrate increasedβ-dilation at low doses of Epi and decreased constriction at higher doses. Intermediate size vessels demonstrate adaptive responses that appear to be a combination of those in larger and smaller vessels. These vascular alterations are evident despite the fact that blood flow does not increase in this muscle during treadmill running and the oxidative capacity of this tissue is not enhanced by treadmill training. Recently, training-induced vascular adaptations have also been observed in the rat intestine; these adaptations include decreased responses to NE and acetylcholine and increased responses to Np. Experimental evidence suggests that vascular smooth muscle adaptations to training are highly dependent on the size and tissue location of the vessel and occur in tissues other than those activated during the training bout. Potential mediators of these adaptations are discussed.

Department of Physiology and Biophysics, Indiana University School of Medicine, Indianapolis, IN 46202

Submitted for publication February 1997.

Accepted for publication May 1997.

Aerobic exercise training has been shown to alter the blood flow distribution among various tissues during acute bouts of exercise(1,9,14). These alterations cannot be explained by training-induced adaptations in cardiac output. Rather, the redistribution of blood flow in trained animals indicates that vascular regulation has also been altered as a result of aerobic training. The mechanisms by which this is accomplished are relatively unknown. Changes in the neural regulation of vascular resistance may produce such alterations in blood flow distribution, and several studies suggest that central and peripheral neural adaptations occur in response to aerobic training(10,18,23). However, the purpose of this review is to examine the possibility that vascular smooth muscle responses to vasoactive stimuli are also altered by aerobic training.

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The vasculature most studied for the effects of aerobic exercise training is that of the coronary circulation. Aerobic exercise training has long been known to decrease coronary vascular resistance, as reflected by changes in coronary blood flow during active and passive conditions (for review, seereference 8). Fewer studies have focused on training-induced alterations in vascular control. An extensive study of coronary artery reactivity by Rogers et al. (20) found a suppression of β-mediated and vasoactive intestinal polypeptide-induced relaxation in isolated vessels from dogs treadmill trained for 11 wk. The constrictor responses of these vessels to norepinephrine and phenylephrine and the endothelial-mediated dilator response to substance P and α2 activation were similar between sedentary and trained groups. In contrast, Oltman et al. (16) found in isolated coronary vessels of trained miniature swine a suppression of constriction in response to norepinephrine, suppression of dilation in response to nitroprusside, and enhancement of dilation in response to adenosine. These training-related alterations in vascular reactivity were found to be maintained after the removal of the endothelial lining, suggesting that the training-related adaptations had included the vascular smooth muscle cells. Training-related alterations in vascular smooth muscle cell regulation were also evident in isolated resistance arteries of trained miniature swine, which demonstrated an enhancement of myogenic constriction (1).

In contrast to the results of Rogers et al. (20), Muller et al. (12) reported an enhanced endothelial-dependent dilator response to bradykinin in the isolated resistance arteries of trained swine. They also found no differences between sedentary and trained animals in the dilator responses to adenosine and nitroprusside. However, Oltman et al. (17) subsequently found no training-related changes in endothelial-mediated vasodilation in isolated proximal coronary arteries of miniature swine. Finally, a set of reports by Wang et al. (25) and Sessa et al.(21) indicate that endothelium-mediated dilation and endothelial cell nitric oxide gene expression are enhanced in dog coronary arterial vessels after 7-10 d of treadmill training. These apparently discrepant results added much confusion to the evaluation of the training-induced adaptations of the coronary vasculature.

In a 1994 review of the effects of exercise training on the coronary circulation, Parker et al. (19) suggested that the adaptations were highly dependent on the location of the vessel within the branching pattern. A summary of the data discussed in that review, as well as other related studies, is presented in Table 1. These results illustrate the apparent order-specificity of the vascular adaptations to aerobic training. For example, vascular smooth muscle relaxation in response to adenosine is enhanced in the proximal and intermediate vessels, but there is no concomitant change apparent in the smaller resistance vessels. A similar, but inverted, pattern can be seen in the endothelial-dependent responses to bradykinin; vascular smooth muscle relaxation in response to bradykinin is enhanced by training in the intermediate and resistance vessels, but not in the larger proximal vessels. Parker et al.(19) conclude that just as the primary mechanisms responsible for vascular regulation differ among branch orders, so do the adaptations to exercise training. It is also important to consider that the surrounding parenchymal tissue and the impending mechanical forces may vary considerably along the vascular tree. At this point it is not apparent whether the order-specificity of the vascular adaptations to exercise training result from the presence of different stimuli at various locations along the vascular tree or to differences in the amenability of the vascular cells to a common exercise-related stimulus for adaptations.

In a 1995 review by Laughlin (7), attention is also brought to the time-dependent nature of the observed coronary vascular adaptations to aerobic training. A summary of that discussion is presented inFigure 1. Essentially, the experimental results indicate that flow-induced and endothelial-mediated dilation is enhanced in the proximal coronary vessels within the first 7-10 d of training. However, this response is short lived, as no differences are found between sedentary and trained animals after 11-20 wk of training. In contrast, the adaptations of the coronary micro-circulation take longer to develop, and after 11-20 wk of training, flow-induced and endothelial-mediated dilation are enhanced in the smaller vessels of trained animals.

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Few studies have looked specifically at vascular regulation in skeletal muscle tissues in sedentary and aerobically trained animals or humans. A 1981 study by Wiegman et al. (26) evaluated the effects of swim training on the in vivo arteriolar responses of the rat cremaster. In this study, arteriolar constriction in response to norepinephrine was reduced in trained rats compared with sedentary rats. However, the unique structure and function of this muscle likely limits extrapolation of these results to other skeletal muscle vascular beds. Lash et al. (6) found enhanced neural-mediated constriction of the hindlimb vascular bed of trained rats after 8-10 wk of treadmill running. However, they found no differences in the direct constrictor effects of phenylephrine. Green et al. (2) also found no differences between sedentary and trained humans in the forearm vascular responses to endothelial-dependent or endothelial-independent dilators. While these studies fail to reflect significant agonist-specific vascular adaptations to exercise training, adaptations specific to muscle type or vessel size can be easily obscured by such gross measurements of vascular resistance. Finally, Sun et al. (22) and Koller et al. (3) found enhanced spontaneous tone and endothelial-dependent dilation in isolated arterioles from the gracilis muscle from rats treadmill trained for 4 wk. However, there were no differences in nitroprusside- or sodium nitrite-induced dilation or norepinephrine-mediated constriction. These studies are obviously more sensitive than the “whole organ” studies previously cited and reflect arteriolar adaptations in a skeletal muscle more “typical” in structure and function than the cremaster. However, when considered together, these various results are contradictory, and most fail to support a training-induced adaptation of the vascular smooth muscle in skeletal muscle tissues.

Lash and Bohlen (4,5) have studied the effects of aerobic training on vascular responses in the rat spinotrapezius muscle. This muscle, which originates along the thoracic spine and inserts into the scapula, is involved in forearm stabilization and movement and was therefore considered likely to be recruited during treadmill running. The thin cross section of this muscle makes it suitable for in vivo visualization of at least four orders of arterial vessels. Lash and Bohlen(4) have found that 8 wk of treadmill training enhances contraction-induced vasodilation in the rat spinotrapezius muscle; these results are comparable to the enhanced flows observed during running or stimulation-induced contractions in the oxidative hindlimb muscles of treadmill trained animals (1,9). These authors(5) have also examined the responses of the rat spinotrapezius muscle arterial vessels to acetylcholine and nitroprusside; these results are presented in Figure 2. After 8 wk of training, there were no differences between sedentary and trained animals in the responses of the large- or intermediate-sized arterioles to nitroprusside. In addition, the responses of these vessels to acetylcholine were actually suppressed in trained rats relative to their sedentary counterparts. In contrast, terminal feed artery dilation in response to nitroprusside was enhanced in trained rats, while the response to acetylcholine was unchanged. As with the coronary circulation, an order- or size-dependent specificity was apparent in the adaptations of the skeletal muscle vasculature to exercise training.

Lash and Bohlen (5) further examined the vascular responses of the rat spinotrapezius muscle vasculature after 16 wk of treadmill training. These results are presented in Figure 3. At this point in time the arteriolar response to acetylcholine was greatly enhanced in trained animals relative to their sedentary counterparts. In addition, the enhanced response of the terminal feed artery to nitroprusside observed after 8 wk of training was not only maintained, but enhanced, after 16 wk of training. Further, after 16 wk of training, the larger arteriolar vessels also demonstrated increased dilation in response to nitroprusside. These results also reflect an order-specificity of the vascular adaptations to exercise training. In addition, a time-dependent expression of the vascular adaptations is apparent in the rat spinotrapezius muscle that is comparable with that observed in the coronary circulation; there is a gradual development of the enhanced endothelial-dependent dilation in the micro-circulation. Importantly, this study demonstrates that vascular smooth muscle adaptations do occur in skeletal muscle tissues in response to exercise training.

Preliminary results from Lash (unpublished results) indicate that additional adaptations of vascular smooth muscle regulation occur in the rat spinotrapezius muscle. Dilation in response to adenosine appears to be diminished in the smaller arterioles, whereas β-mediated dilation appears to be enhanced in these vessels; α-mediated constriction appears to be enhanced at the three vascular levels examined. The order specificity of training-induced vascular adaptations remains consistently evident in these studies.

A primary limitation to the extrapolation of the studies by Lash and Bohlen(4,5) to other skeletal muscle tissues is the fact that they have failed to find a consistent enhancement of the oxidative capacity of the rat spinotrapezius muscle in response to training(4,5). This leads to the questions: 1) Is the rat spinotrapezius muscle recruited during treadmill running? and 2) Is it“representative” of other “trained” skeletal muscle tissues? Recent work by Musch and Poole (1) indicates that blood flow to the rat spinotrapezius muscle is not increased during treadmill running relative to that observed at rest. The conclusion suggested by these combined results is that vascular smooth muscle cell and endothelial cell adaptations may occur in a skeletal muscle tissue that is not recruited during isolated training bouts. Further, it is possible the vascular adaptations that occur in recruited skeletal muscles differ from those that occur in nonactive muscles. And, finally, we are left with the question, what stimuli are responsible for vascular adaptations in nonrecruited skeletal muscles? The adaptations observed in the rat spinotrapezius muscle occur in the absence of temporary increases in blood flow in response to acute running.

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The changes in blood flow distribution during exercise that have been observed in aerobically trained animals are not limited to skeletal muscle tissues (1). During the transition from rest to exercise, blood flows to the splanchnic organs and to the kidneys decrease. However, for the same absolute exercise intensity, this decrease in blood flow is less in trained animals than in their sedentary counterparts. Therefore, blood flows to the kidneys and splanchnic organs are higher in trained, than sedentary, animals at comparable running speeds. However, renal and splanchnic blood flows are similar between sedentary and trained groups, or slightly lower in trained animals, when each is exercising at maximal levels. These differences in blood flow regulation could be attributed to changes in central neural activity or to changes in vascular reactivity.

Lash et al. (6) evaluated intestinal resistance in sedentary and trained rats during baroreflex activation (carotid artery occlusion) and systemic infusion of phenylephrine, an α-agonist. In this study, they also controlled for pressure-induced amplification of the constrictor response. In the intestine of trained rats, there was a decrease in the vascular response to phenylephrine and an enhanced pressure-dependent amplification of vasoconstriction; neural mediation of the baroreflex was not different between sedentary and trained groups. These results suggest that in the intestinal vasculature α-adrenergic constriction is suppressed and myogenic constrictor mechanisms are enhanced by aerobic exercise training.

Preliminary evidence from studies of the intestinal microvasculature of sedentary and trained rats supports the whole organ studies (Lash, unpublished observations). The largest arterioles in the small intestine appear to constrict less in trained than sedentary rats when exposed to locally applied norepinephrine. In addition, these preliminary studies suggest that the vasodilator response to sodium nitroprusside is enhanced in intermediate size intestinal arterioles of trained animals and that the endothelial response to acetylcholine application is suppressed. Therefore, it appears that, as a result of aerobic exercise training, adaptations of vasoregulatory mechanisms occur in the vasculature of nonmuscle tissues.

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These studies indicate that aerobic exercise training induces adaptations of vascular reactivity in a variety of organ tissues. Such adaptations certainly occur in active muscle tissue such as the heart. However, the experimental evidence also demonstrates that such adaptations may occur in inactive skeletal muscle tissues (4,5) and in visceral organs ((6) and J. M. Lash, unpublished observations). The specific type of vasoregulatory adaptation expressed appears to be highly dependent on the location of the vessel, both in relation to the tissue in which the vessel is embedded and its position along the vascular branching pattern. In addition to the location specificity of the adaptations, there seems to be a time-course for the development of vascular adaptations to aerobic exercise training. Some adaptations occur within a few days of the initiation of the training regimen(3,21,22,25). However, these adaptations may be transient, as different alterations of vascular function are observed with prolonged exercise training.

The physiological relevance of these training-induced vascular adaptations may be evidenced in studies of whole organ blood flows in exercising animals. When compared with their sedentary counterparts, coronary blood flows are enhanced in trained animals during exercise (14). These results are consistent with the enhanced endothelial-dependent and endothelial-independent dilation of coronary vessels as presented inTable 1. With regard to skeletal muscle, Armstrong and Laughlin (1) found fiber-type specific adaptations of exercise blood flow in trained rats. At comparable submaximal exercise intensities, blood flows to slow-twitch and red fast-twitch muscle fibers in the hindlimb were higher in trained than sedentary rats, whereas blood flows to mixed and white fast-twitch fibers were lower in trained rats. During maximal exercise, Musch et al. (14) found that blood flow to the gastrocnemius muscle of dogs was increased after aerobic training, whereas flow to the nonlocomotor temporalis muscle was decreased. It is important to note that the trained dogs were exercising at a 30% higher maximal capacity. The enhanced flows observed to specific skeletal muscles are consistent with the increased functional dilation observed in the rat spinotrapezius muscle, as well as the training-induced enhanced dilation observed in response to epinephrine, nitroprusside, and acetylcholine(Table 2). The decreased blood flows are consistent with the enhanced adrenergic and myogenic constriction observed in the rat spinotrapezius muscle and hindlimb of trained animals, respectively. With regard to the intestine, during submaximal exercise, blood flow is generally higher in trained than sedentary animals (1). In contrast, at maximal exercise splanchnic flows are lower in trained animals(14). The enhanced flow during submaximal exercise is consistent with the suppressed adrenergic constriction observed in the rat intestine, as well as the enhanced dilation in response to nitroprusside(6; J. M. Lash, unpublished observations). The lower intestinal blood flow observed in trained animals during maximal exercise could be related to the suppressed dilator response to the endothelial-dependent dilator acetylcholine or to the enhanced myogenic constrictor response to elevations in blood pressure. While such causal attributions can be postulated, there have been no studies directly linking specific changes in vascular reactivity with changes in blood flow regulation.

Several questions remain to be answered regarding the vascular adaptations to exercise training. First, what vascular adaptations occur in“trained” skeletal muscle tissues? As noted above, treadmill training does not enhance citrate synthase activity in the rat spinotrapezius muscle (4,5), and there appears to be no hyperemic response in this tissue during running (15). Although not specifically reported in the studies of isolated arterioles from the rat gracilis muscle (3,22), data from other laboratories indicate that there are only transient increases in rat gracilis muscle blood flow during treadmill running (1) and the oxidative capacity of the rat gracilis muscle is not significantly enhanced by treadmill training (4). It will be important to identify a skeletal muscle that is “trained” in the traditional sense and that is amenable to in vivo or in vitro vascular observations. Second, to what extent is there a “whole-body” vascular adaptation to aerobic exercise training? The evidence indicates that vascular adaptations occur in tissues not directly involved in the exercise bout. However, these vascular adaptations are not uniform throughout the body, or even throughout a single tissue. Studies of other vascular beds, e.g., renal or cerebral, may reveal additional “whole-body” vascular adaptations. Third, what are the stimuli responsible for the vascular adaptations to exercise training? The differential adaptations observed in various tissues may be related to the differing stimuli to which these vessels are exposed. For example, changes in blood flow velocity through a vessel lumen are known to induce alterations in vascular reactivity (11), during aerobic exercise blood flow is increased in active skeletal muscle tissues and is decreased in the intestine. Other such stimuli may include changes in wall shear stress, wall tension, or the local concentrations of vasoactive biochemicals. Such stimuli may account for the apparent tissue-specific nature of the vascular adaptations to training. However, the order-dependent specificity of these adaptations is a bit more complex and may reflect differences in the responsiveness of the vascular smooth muscle cells along the vascular tree. In any case, the current evidence indicates that no single vessel or tissue accurately reflects adaptations throughout the vascular system. Finally, what cellular mechanisms are responsible for the changes in vascular reactivity that occur as a result of exercise training? The cellular mechanisms that are altered may include changes in receptor number and second messenger systems, changes in actin/myosin alignment or binding, or changes in the mechanical properties of the vessel wall. Underwood et al. (24) have described changes in the calcium regulation of coronary vessels from trained miniature swine, suggesting that, at least in some vessels, intracellular regulatory mechanisms are altered by aerobic exercise training. The tissue- and order-specificity of the vascular adaptations to training suggest these cellular modifications also likely differ among vessel types. This review demonstrated that the vascular adaptations to exercise training are extremely complex and will require a great deal of further investigation.

The author would like to thank Dr. H. Glenn Bohlen for his support of this work.

This work was supported by NIH grant HL-47483.

Address for correspondence: J. M. Lash, Department of Physiology & Piophysics, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202.

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