title: ATP-induced vasodilation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins, and adenosine.
abstract: Plasma ATP is thought to contribute to the local regulation of skeletal muscle blood flow. Intravascular ATP infusion can induce profound limb muscle vasodilatation, but the purinergic receptors and downstream signals involved in this response remain unclear. This study investigated: 1) the role of nitric oxide (NO), prostaglandins, and adenosine as mediators of ATP-induced limb vasodilation and 2) the expression and distribution of purinergic P(2) receptors in human skeletal muscle. Systemic and leg hemodynamics were measured before and during 5-7 min of femoral intra-arterial infusion of ATP [0.45-2.45 micromol/min] in 19 healthy male subjects with and without coinfusion of N(G)-monomethyl-l-arginine (l-NMMA; NO formation inhibitor; 12.3 +/- 0.3 (SE) mg/min), indomethacin (INDO; prostaglandin formation blocker; 613 +/- 12 microg/min), and/or theophylline (adenosine receptor blocker; 400 +/- 26 mg). During control conditions, ATP infusion increased leg blood flow (LBF) from baseline conditions by 1.82 +/- 0.14 l/min. When ATP was coinfused with either l-NMMA, INDO, or l-NMMA + INDO combined, the increase in LBF was reduced by 14 +/- 6, 15 +/- 9, and 39 +/- 8%, respectively (all P < 0.05), and was associated with a parallel lowering in leg vascular conductance and cardiac output and a compensatory increase in leg O(2) extraction. Infusion of theophylline did not alter the ATP-induced leg hyperemia or systemic variables. Real-time PCR analysis of the mRNA content from the vastus lateralis muscle of eight subjects showed the highest expression of P(2Y2) receptors of the 10 investigated P(2) receptor subtypes. Immunohistochemistry showed that P(2Y2) receptors were located in the endothelium of microvessels and smooth muscle cells, whereas P(2X1) receptors were located in the endothelium and the sacrolemma. Collectively, these results indicate that NO and prostaglandins, but not adenosine, play a role in ATP-induced vasodilation in human skeletal muscle. The expression and localization of the nucleotide selective P(2Y2) and P(2X1) receptors suggest that these receptors may mediate ATP-induced vasodilation in skeletal muscle.
authors.affiliation: The Copenhagen Muscle Research Centre, Rigshospitalet, Section 7652, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. stefan@cmrc.dk
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Mortensen
authors.forename: José
authors.initials: J
authors.lastname: González-Alonso
authors.forename: Laurids T
authors.initials: LT
authors.lastname: Bune
authors.forename: Bengt
authors.initials: B
authors.lastname: Saltin
authors.forename: Henriette
authors.initials: H
authors.lastname: Pilegaard
authors.forename: Ylva
authors.initials: Y
authors.lastname: Hellsten
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000378:metabolism*; D000328:Adult; D001783:Blood Flow Velocity; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D035002:Lower Extremity; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058469:Receptors, Purinergic P2X; D058473:Receptors, Purinergic P2Y2; D012039:Regional Blood Flow; D015398:Signal Transduction / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D055815:Young Adult; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; C546385:P2RY2 protein, human; D011453:Prostaglandins; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D058473:Receptors, Purinergic P2Y2; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D013806:Theophylline; D019001:Nitric Oxide Synthase; D000241:Adenosine; D007213:Indomethacin