title: Lidocaine relaxation in isolated rat aortic rings is enhanced by endothelial removal: possible role of Kv, KATPchannels and A2areceptor crosstalk.
abstract: Lidocaine is an approved local anesthetic and Class 1B antiarrhythmic with a number of ancillary properties. Our aim was to investigate lidocaine's vasoreactivity properties in intact versus denuded rat thoracic aortic rings, and the effect of inhibitors of nitric oxide (NO), prostenoids, voltage-dependent Kvand KATPchannels, membrane Na+/K+pump, and A2aand A2breceptors.
  
  
  
  Aortic rings were harvested from adult male Sprague Dawley rats and equilibrated in an organ bath containing oxygenated, modified Krebs-Henseleit solution, pH 7.4, 37 °C. The rings were pre-contracted sub-maximally with 0.3 μM norepinephrine (NE), and the effect of increasing lidocaine concentrations was examined. Rings were tested for viability after each experiment with maximally dilating 100 μM papaverine. The drugs 4-aminopyridine (4-AP), glibenclamide, 5-hydroxydecanoate, ouabain, 8-(3-chlorostyryl) caffeine and PSB-0788 were examined.
  
  
  
  All drugs tested had no significant effect on basal tension. Lidocaine relaxation in intact rings was biphasic between 1 and 10 μM (Phase 1) and 10 and 1000 μM (Phase 2). Mechanical removal of the endothelium resulted in further relaxation, and at lower concentrations ring sensitivity (% relaxation per μM lidocaine) significantly increased 3.5 times compared to intact rings. The relaxing factor(s) responsible for enhancing ring relaxation did not appear to be NO- or prostacyclin-dependent, as L-NAME and indomethacin had little or no effect on intact ring relaxation. In denuded rings, lidocaine relaxation was completely abolished by Kvchannel inhibition and significantly reduced by antagonists of the MitoKATPchannel, and to a lesser extent the SarcKATPchannel. Curiously, A2asubtype receptor antagonism significantly inhibited lidocaine relaxation above 100 μM, but not the A2breceptor.
  
  
  
  We show that lidocaine relaxation in rat thoracic aorta was biphasic and significantly enhanced by endothelial removal, which did not appear to be NO or prostacyclin dependent. The unknown factor(s) responsible for enhanced relaxation was significantly reduced by Kvinhibition, 5-HD inhibition, and A2asubtype inhibition indicating a potential role for crosstalk in lidocaine's vasoreactivity.
authors.affiliation: Heart, Trauma and Sepsis Research Laboratory, Australian Institute of Tropical Health and Medicine, College of Medicine and Dentistry, James Cook University, 1 James Cook Drive, 4811, Queensland, Australia.|Physiology Department, Medical Faculty, Hasanuddin University, Jl. Perintis Kemerdekaan, Km. 10, 90213, Tamalanrea, Makassar, Indonesia.
authors.forename: Aryadi
authors.initials: A
authors.lastname: Arsyad
authors.affiliation: Heart, Trauma and Sepsis Research Laboratory, Australian Institute of Tropical Health and Medicine, College of Medicine and Dentistry, James Cook University, 1 James Cook Drive, 4811, Queensland, Australia. geoffrey.dobson@jcu.edu.au.
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Dobson
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D002110:Caffeine / Q000031:analogs & derivatives / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000037:antagonists & inhibitors; D005905:Glyburide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D054086:KATP Channels / Q000037:antagonists & inhibitors*; D008012:Lidocaine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009638:Norepinephrine / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010208:Papaverine / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D003652:Decanoic Acids; D006880:Hydroxy Acids; D054086:KATP Channels; D024642:Potassium Channels, Voltage-Gated; D043705:Receptor, Adenosine A2A; C081320:8-(3-chlorostyryl)caffeine; D009569:Nitric Oxide; D002110:Caffeine; D010042:Ouabain; C052853:5-hydroxydecanoic acid; D008012:Lidocaine; D015761:4-Aminopyridine; D010208:Papaverine; D011464:Epoprostenol; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine; D007213:Indomethacin
keywords: Endothelium; Lidocaine; Nitric oxide; Rat aorta; Redox stress; Relaxation; Vasodilation