K(ATP) channels and NO dilate redundantly intramuscular arterioles during electrical stimulation of the skeletal muscle in mice

Functional hyperemia is fundamental to provide enhanced oxygen delivery during exercise in skeletal muscle. Different mechanisms are suggested to contribute, mediators from skeletal muscle, transmitter spillover from the neuromuscular synapse as well as endothelium-related dilators. We hypothesized that redundant mechanisms that invoke adenosine, endothelial autacoids, and K(ATP) channels mediate the dilation of intramuscular arterioles in mice. Arterioles (maximal diameter: 20–42 µm, n = 65) were studied in the cremaster by intravital microscopy during electrical stimulation of the motor nerve to induce twitch or tetanic skeletal muscle contractions (10 or 100 Hz). Stimulation for 1–60 s dilated arterioles rapidly up to 65% of dilator capacity. Blockade of nicotinergic receptors blocked muscle contraction and arteriolar dilation. Exclusive blockade of adenosine receptors (1,3-dipropyl-8-(p-sulfophenyl)xanthine) or of NO and prostaglandins (nitro-L-arginine and indomethacin, LN + Indo) exerted only a minor attenuation. Combination of these blockers, however, reduced the dilation by roughly one-third during longer stimulation periods (> 1 s at 100 Hz). Blockade of K(ATP) channels (glibenclamide) which strongly reduced adenosine-induced dilation reduced responses upon electrical stimulation only moderately. The attenuation was strongly enhanced if glibenclamide was combined with LN + Indo and even observed during brief stimulation. LN was more efficient than indomethacin to abrogate dilations if combined with glibenclamide. Arteriolar dilations induced by electrical stimulation of motor nerves require muscular contractions and are not elicited by acetylcholine spillover from neuromuscular synapses. The dilations are mediated by redundant mechanisms, mainly activation of K(ATP) channels and release of NO. The contribution of K(+) channels and hyperpolarization sets the stage for ascending dilations that are crucial for a coordinated response in the network.