title: Pannexin-1 channels do not regulate α1-adrenoceptor-mediated vasoconstriction in resistance arteries.
abstract: Recent reports have provided evidence for a new concept that in small resistance arteries α1D-adrenoceptor-mediated contraction is intimately linked to pannexin-1 (Px1) hemichannels that open to allow the release of ATP, from the smooth muscle effector cell, that acts back on P2Y purinoceptors to cause contraction. This concept mainly relied on using mefloquine 10-20μM as a putative selective Px1 channel-blocking agent to completely inhibit the contraction to phenylephrine, but not K(+) 40mM. Lower concentrations of mefloquine had no effect. The purpose of the present study was to explore the specificity of mefloquine for Px1 channels and the role of these channels in small artery contraction. In mouse and rat isolated small resistance arteries, either pressurised or set up for wire myography, the effects of mefloquine on contractions to K(+), phenylephrine and a range of vasoconstrictor agents were assessed and compared with the Px1 channel inhibitor carbenoxolone. Mefloquine had a wide range of inhibitory actions at 10-20μM, some 200-fold above the concentrations previously shown to inhibit expressed Px1 channel activity. Mefloquine 3-10μM inhibited phenylephrine, U46619, vasopressin, endothelin-1, sympathetic nerve stimulation and K(+) 40mM-mediated contractions in rat and mouse small mesenteric, and mouse thoracodorsal, arteries. Carbenoxolone 1-100μM did not inhibit the contractile responses to these agents in small resistance arteries. The present study demonstrates that in small resistance arteries there is no evidence that Px1 channels releasing ATP have any role in the constrictor actions of α1-adrenoceptor activation.
authors: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: jamesaa@unimelb.edu.au.
authors: James A
authors: JA
authors: Angus
authors: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: a.betrie@student.unimelb.edu.au.
authors: Ashenafi H
authors: AH
authors: Betrie
authors: Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: cewright@unimelb.edu.au.
authors: Christine E
authors: CE
authors: Wright
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000294:innervation / Q000378:metabolism / Q000502:physiology*; D002229:Carbenoxolone / Q000494:pharmacology; D017630:Connexins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015767:Mefloquine / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000294:innervation / Q000378:metabolism / Q000502:physiology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D017630:Connexins; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D018340:Receptors, Adrenergic, alpha-1; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D002229:Carbenoxolone; D015767:Mefloquine
keywords: ATP release; Carbenoxolone; Carbenoxolone disodium salt (PubChem CID: 6419769); Mefloquine; Mefloquine hydrochloride (PubChem CID: 65329); Pannexin-1 channels; Phenylephrine hydrochloride (PubChem CID: 5284443); Vasoconstriction; α(1)-adrenoceptors