title: Effect of purinergic receptor activation on Na+-K+ pump activity, excitability, and function in depolarized skeletal muscle.
abstract: Activity-induced elevation of extracellular purines and pyrimidines has been associated with autocrine and paracrine signaling in many tissues. Here we investigate the effect of purinergic signaling for the excitability and contractility of depolarized skeletal muscle. Muscle excitability was experimentally depressed by elevating the extracellular K(+) from 4 to 10 mM, which reduced the tetanic force to 24 +/- 2% of the force at 4 mM K(+). Upon addition of 1 mM ATP, however, the force recovered to 65 +/- 8% of the control force (P < 0.001, n = 5). A similar recovery was seen with ADP, but not with UTP or adenosine. The ATP-induced force recovery could be inhibited by P2Y(1) receptor antagonists (3 muM SCH-202676 or 1 muM MRS-2500). A fourfold increase in M-wave area demonstrated that the ATP-induced force recovery was associated with restoration of muscle excitability (P < 0.05, n = 4). Experiments using (86)Rb(+) as a tracer for K(+) showed that ATP also induced a twofold increase in the activity of muscle Na(+)-K(+) pumps. The force recovery and the stimulation of the Na(+)-K(+) pump activity by ATP were inhibited by 50 muM of the phospholipase C inhibitor U-73122. It is concluded that purinergic signaling can increase the Na(+)-K(+) pump activity and improve force and excitability of depolarized skeletal muscles. This novel purinergic regulation may be important for the maintenance of muscle excitability during intense exercise, where the extracellular K(+) can increase substantially.
authors.affiliation: Department of Physiology and Biophysics, Aarhus University, Denmark. mbl@fi.au.dk
authors.forename: Martin
authors.initials: M
authors.lastname: Broch-Lips
authors.forename: Thomas Holm
authors.initials: TH
authors.lastname: Pedersen
authors.forename: Ole Baekgaard
authors.initials: OB
authors.lastname: Nielsen
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D056966:Excitation Contraction Coupling / Q000187:drug effects; D008564:Membrane Potentials; D009119:Muscle Contraction / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D058914:Purinergic Antagonists; D011687:Purines / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011983:Receptors, Purinergic / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology; D013997:Time Factors; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014544:Uridine Triphosphate / Q000378:metabolism
chemical_list: C495475:2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate; D003838:Deoxyadenine Nucleotides; D004963:Estrenes; D010726:Phosphodiesterase Inhibitors; D058914:Purinergic Antagonists; D011687:Purines; D011760:Pyrrolidinones; D011983:Receptors, Purinergic; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; C418425:SCH-202676; D013830:Thiadiazoles; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D010738:Type C Phospholipases; D000254:Sodium-Potassium-Exchanging ATPase; D000241:Adenosine; D011188:Potassium; D014544:Uridine Triphosphate