Lidocaine relaxation in isolated rat aortic rings is enhanced by endothelial removal: possible role of Kv, KATP channels and A2a receptor crosstalkReport as inadecuate




Lidocaine relaxation in isolated rat aortic rings is enhanced by endothelial removal: possible role of Kv, KATP channels and A2a receptor crosstalk - Download this document for free, or read online. Document in PDF available to download.

BMC Anesthesiology

, 16:121

General pharmacology and pharmacokinetics

Abstract

BackgroundLidocaine 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 Kv and KATP channels, membrane Na-K pump, and A2a and A2b receptors.

MethodsAortic 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.

ResultsAll 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 factors 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 Kv channel inhibition and significantly reduced by antagonists of the MitoKATP channel, and to a lesser extent the SarcKATP channel. Curiously, A2a subtype receptor antagonism significantly inhibited lidocaine relaxation above 100 μM, but not the A2b receptor.

ConclusionsWe 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 factors responsible for enhanced relaxation was significantly reduced by Kv inhibition, 5-HD inhibition, and A2a subtype inhibition indicating a potential role for crosstalk in lidocaine’s vasoreactivity.

KeywordsRat aorta Lidocaine Relaxation Vasodilation Endothelium Nitric oxide Redox stress Abbreviations4-AP4-aminopyridine

5 HD5-Hydroxydecanoate

CSC8-3-chlorostyryl caffeine

MitoKATPMitochondrial KATP channel

NENorepinephrine

NONitric oxide

PSB-07888-4-4-4-chlorobenzylpiperazine-1-sulfonylphenyl-1-propylxanthine

SarcKATPSarcoplasmic KATP channel

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Author: Aryadi Arsyad - Geoffrey P. Dobson

Source: https://link.springer.com/







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