Adenosine and nitric oxide in exercise-induced human skeletal muscle vasodilatation

The vasoactive substances adenosine and nitric oxide (NO) are credible cand idates in the local regulation of skeletal muscle blood flow. Adenosine and NO have both been shown to increase in skeletal muscle cells and interstit ial fluid during exercise and the enzymes responsible for their formation, AMP 5'-nucleotidase and NO synthase (NOS), have been shown to be activated upon muscle contraction. In vitro as well as in vivo evidence suggest that the contraction-induced increase in interstitial adenosine concentration la rgely stems from extracellular formation via the membrane-bound ecto-form o f AMP 5'-nucleotidase. It remains unclear whether the exercise-induced NO f ormation in muscle originates from endothelial NOS in the microvascular end othelium, or from neuronal NOS (nNOS) in nerve cells and muscle fibres. Fun ctional evidence for the role of adenosine in muscle blood flow control ste ms from studies using adenosine receptor agonists and antagonsits, adenosin e deaminase or adenosine uptake inhibitors. The majority of these studies h ave been performed on laboratory animals and, although the results show som e discrepancy, the majority of studies indicate that adenosine does partici pate in the regulation of muscle blood flow. In humans, evidence is lacking . The role of NO in the regulation of skeletal muscle blood flow has mainly been studied using NOS inhibitors. Despite a large number of studies in th is area, the role of NO for the contraction-induced increase in skeletal mu scle blood flow is uncertain. The majority, but not all, human and animal s tudies show that, whereas blockade of NOS reduces muscle blood flow at rest and in recovery from exercise, there is no effect on the exercise-induced increase in muscle perfusion. Conclusive evidence for the mechanisms underl ying the precise regulation of the multiphased increase in skeletal muscle blood flow during exercise and the role and potency of various vasoactive s ubstances, remain missing.