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(Circulation. 2005;111:2748-2751.)
© 2005 American Heart Association, Inc.

Heart Failure

Interstitial ATP and Norepinephrine Concentrations in Active Muscle

From the Division of Cardiology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey (J.L., N.C.K., L.I.S.), and Lebanon Veterans Affairs Medical Center, Lebanon, Pa (L.I.S.).

Correspondence to Jianhua Li, PhD, Division of Cardiology, H047, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, 500 University Dr, Hershey, PA 17033. E-mail jzl10{at}psu.edu

Received October 1, 2004; revision received December 13, 2004; accepted January 20, 2005.

Background— Sympathetic nervous system activity increases with exercise in normal subjects. Heightened peripheral sympathetic nervous activity and the resultant increased neurovascular levels of norepinephrine (NE) evoke vasoconstriction and serve to maintain blood pressure and perfusion to vital organs. Previous work demonstrated that the interstitial ATP concentrations ([ATP]i) rise in contracting skeletal muscle, and it is known that sympathetic nerves have purinergic P2X receptors. Thus, in this report we tested the hypothesis that elevated ATP would stimulate these receptors and increase interstitial NE concentrations ([NE]i).

Methods and Results— Muscle interstitial samples were collected from microdialysis probes inserted in the skeletal muscle of rats, and dialysate concentrations of ATP and NE were determined by the high-performance liquid chromatography method. Stretch (0.5 kg of tension) increased [ATP]i by 68% (P<0.05) and [NE]i by 45% (P<0.05) in active muscle. The rise in NEi was linearly linked to the elevated ATPi (r=0.878, P<0.001). [NE]i was also elevated by 76% (P<0.05) after ATP (3 µmol/L) was injected into the arterial blood supply of the hindlimb muscles. The [NE]i response to muscle stretch was blunted after the P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) was given. Finally, this response was potentiated by the nucleotidase inhibitor 6-N,N-diethyl-ß--dibromomethylene-D-adenosine-5'-triphosphate (ARL67156.

Conclusions— ATPi released by skeletal muscle during stretch stimulates P2X receptors on the sympathetic nerves and increases the concentration of NEi in the muscle interstitium.

Key Words: nervous system, sympathetic • exercise • blood flow

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