Background and purpose: Transient lower oesophageal sphincter relaxations (TLESRs) are triggered by activation of mechanosensitive gastric vagal afferents and are the major cause of gastroesophageal reflux and therefore an important target for therapeutic intervention in gastroesophageal reflux disease (GERD). Activation of the metabotropic GABA B receptor has shown to inhibit TLESRs. The aim of the present study was to assess the role of the ionotropic GABA A receptor in the regulation of TLESRs. Experimental approach: TLESRs were quantified using Dentsleeve manometry in dogs, and GABA A agonists were given i.v. prior to gastric distension. Immunohistochemistry and RT-PCR were used to localize GABA A receptors in the dog nodose ganglion, the source of vagal afferents which initiate TLESRs. Key results: The prototypical GABA A agonist muscimol produced a dose-dependent inhibition of TLESRs ranging from 19 to 56%. The two other GABA A agonists evaluated, isoguvacine and 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP), as well as the GABA A positive allosteric modulator diazepam, had no major effects on TLESRs. Evaluation of higher doses was limited by emesis (THIP and isoguvacine) or restlessness/sedation (diazepam). Of the predominant GABA A receptor subunits (a, b and g components), a and b but not g were detected in the dog nodose ganglion by RT-PCR, while immunohistochemistry in addition demonstrated nerve fibres expressing the g subunit. Conclusions and implications:The present observations demonstrate that GABA A receptors exert an inhibitory control of TLESRs. These results warrant further studies using GABA A isoform-selective agonists to define the identity of receptors involved.

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Mice lacking G-protein-coupled receptor 55 (GPR55) exhibit impaired contractile reserve and age-related systolic dysfunction, implying a role for this receptor in cardiac physiology/pathophysiology. To investigate the role of GPR55 in atherosclerosis-induced alterations in cardiac function, male and female, C57BL/6, ApoE-/-, GPR55-/- and ApoE-/-/GPR55-/- mice were fed a normal diet (ND) or high fat diet (HFD) for 12 weeks. Post-diet, indices of cardiac function were measured under anaesthesia via pressure-volume loop (PVL) analysis prior to harvesting blood and tissues for ex vivo analysis. Neither C57BL/6 nor GPR55-/- mice developed significant atherosclerotic plaques in the thoracic aorta, in response to HFD. ApoE-/- HFD mice demonstrated significant plaque deposition whereas ApoE-/-/GPR55-/- mice developed fewer plaques in response to HFD, suggesting GPR55 plays a detrimental role in atherogenesis. In contrast, while baseline systolic function (ejection fraction; EF and Emax) in ApoE-/- and GPR55-/- was similar to that in C57BL/6 mice, regardless of diet, high fat feeding in ApoE-/-/GPR55-/- mice caused a reduction systolic function, indicative of an important role for GPR55 in maintaining cardiac function in the hyperlipidaemic heart. Both ApoE-/- and ApoE-/-/GPR55-/- mice had similarly elevated LDL:HDL ratios, irrespective of diet, while GPR55-/- mice had similar LDL:HDL ratios to C57BL/6 mice that were unaffected by HFD. In conclusion, these results indicate that in the presence of high fat feeding, GPR55 has a complex role whereby it promotes atherosclerotic plaque development while maintaining systolic function. Neither of these role appears to be mediated by changes in plasma LDL:HDL ratios.