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-Adrenergic Receptor Responsiveness in Exercising Skeletal Muscle
Department of General Internal Medicine
Section of Gerontology & Geriatrics
Leiden University Medical Center
2300 RC Leiden, The Netherlands
E-mail:a.m.kamper{at}lumc.nl
ABSTRACT
The production of nitric oxide is the putative mechanism for the attenuation of sympathetic vasoconstriction (sympatholysis) in working muscles during exercise. We hypothesized that nitric oxide synthase blockade would eliminate the reduction in 
-adrenergic-receptor responsiveness in exercising skeletal muscle. Ten mongrel dogs were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs and a catheter in one femoral artery. The selective 1-adrenergic agonist (phenylephrine) or the selective 2-adrenergic agonist (clonidine) was infused as a bolus into the femoral artery catheter at rest and during mild and heavy exercise. Before nitric oxide synthase inhibition with NG-nitro-L-arginine methyl ester L-NAME), intra-arterial infusions of phenylephrine elicited reductions in vascular conductance of –91 ± 3, –80 ± 5, and –75 ± 6% (means ± SE) at rest, 3 miles/h, and 6 miles/h and 10% grade, respectively. Intra-arterial clonidine reduced vascular conductance by –65 ± 6, –39 ± 4, and –30 ± 3%. After L-NAME, intra-arterial infusions of phenylephrine elicited reductions in vascular conductance of –85 ± 5, –85 ± 5, and –84 ± 5%, whereas clonidine reduced vascular conductance by –67 ± 5, –45 ± 3, and –35 ± 3%, at rest, 3 miles/h, and 6 miles/h and 10% grade. 1-Adrenergic-receptor responsiveness was attenuated during heavy exercise. In contrast, 2-adrenergic-receptor responsiveness was attenuated even at a mild exercise intensity. Whereas the inhibition of nitric oxide production eliminated the exercise-induced attenuation of 1-adrenergic-receptor responsiveness, the attenuation of 2-adrenergic-receptor responsiveness was unaffected. These results suggest that the mechanism of exercise sympatholysis is not entirely mediated by the production of nitric oxide.
To the Editor: In a recent article, Buckwalter et al. (2) presented the results of the role of nitric oxide and -adrenergic receptor responsiveness in exercising skeletal muscle. The article raises two serious questions.
First, the authors suggest that clonidine is a selective 2-adrenergic receptor agonist. However, it is well known for many years that clonidine also has 1-adrenergic receptor properties (1). Therefore, the interpretation of the effect of clonidine on the blood flow should be seen as a result of both 1- and 2-adrenergic receptor stimulation.
The second question pertains to the interpretation of the data as presented in Table 1. In the experimental limb, the blood flow at rest decreases from 135 ± 18 ml/min before infusion to 11 ± 5 ml/min after infusion of phenylephrine. This difference is significantly different. After exercise (3 miles/h), there is an increase in blood flow to 328 ± 33 ml/min before the infusion of phenylephrine (2.4 times more). At the same exercise level, there is an increase of flow to 73 ± 26 ml/min after the infusion of phenylephrine.This is 6.6 times higher compared with rest. After exercise of 6 miles/h, the difference between baseline and exercise is even more (6.6 before phenylephrine compared with 22 times after phenylephrine). Hence, when we analyze their data in our way, it seems that under 1-adrenergic receptor stimulation the effect of exercise is more enhanced than without 1-adrenergic receptor stimulation. Then it seems that at the highest level of exercise, and possibly also at the lower level of exercise, NG-nitro-L-arginine methyl ester is blocking the increase in blood flow in the experimental limb. If the analysis is performed this way, the results indicate a different conclusion than stated in the article. In summary, we believe that the data as provided and analyzed by the authors can at least be interpreted in different ways.
REFERENCES
1-adrenoceptors. Brit J Pharmacol 74: 757–758, 1981.
Medical College of Wisconsin/Veterans Affairs Medical Center
Milwaukee, Wisconsin 53226
To the Editor: Drs. Kamper and de Craen highlight two issues regarding our recent publication (2). First of all, they take issue with the selectivity of clonidine for 2-adrenergic receptors. We believe that this is more a theoretical than a practical concern. The selectivity has been well demonstrated for the canine skeletal muscle vasculature in a previous study by Horn et al. (3). They found that the magnitude of vasoconstriction elicited by intra-arterial infusion of clonidine was antagonized by the 2-blocker yohimbine but entirely unaffected by the 1-blocker prazosin. Furthermore, we have shown that rauwolscine completely abolishes the vasoconstrictor response to intra-arterial clonidine in the dog hindlimb (1). Even if clonidine acted as a weak agonist for 1-adrenergic receptors, one should realize that it was not the only -adrenergic agonist infused in the present study. When the data from both the clonidine and the phenylephrine infusions are examined together, there is a clear differentiation in the patterns of 1- and 2-adrenergic responsiveness in the skeletal muscle vasculature at rest compared with exercise. Although 1-adrenergic receptor responsiveness (as produced by phenylephrine) was fairly well maintained from rest to exercise, the amount of constriction that could be produced with clonidine was greatly diminished. On the basis of the demonstrated selectivity of clonidine in the canine vasculature and the divergence in the vascular responses to phenylephrine and clonidine in the present study, we feel it would be a mistake to interpret the effect of clonidine as a result of both 1- and 2-receptor stimulation.
Second, Drs. Kamper and de Craen take issue with the analysis and interpretation of the agonist data. It is unfortunate that they misinterpreted the experimental design because exercise was not superimposed on the agonist infusions. Thus their analysis is inappropriate and has little relevance to the tested hypothesis. We stand by our original interpretation of the data that -adrenergic receptor responsiveness was attenuated by exercise, with 2-responsiveness being more attenuated than 1 responsiveness. Inhibition of nitric oxide production eliminated the exercise-induced attenuation of 1-, but not 2-, adrenergic receptor responsiveness.
REFERENCES
-Adrenergic vasoconstriction in active skeletal muscles during dynamic exercise. Am J Physiol Heart Circ Physiol 277: H33–H39, 1999.-adrenergic receptors in the canine resistance vessels. Naunyn Schmiedebergs Arch Pharmacol 318: 166–172, 1982.[CrossRef][ISI][Medline]
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