Clinical studies showed that GABAB receptor agonists improve symptoms in patients with gastroesophageal reflux disease. One proposed mechanism of this effect is direct inhibition of the gastroesophageal vagal tension mechanosensors by GABAB agonists leading to reduction of reflux. In addition to tension mechanosensors, the vagal nodose ganglion supplies the esophagus with nociceptive C-fibers that likely contribute to impairment of esophageal reflex regulation in diseases. We hypothesized that GABAB agonists inhibit mechanically-induced activation of vagal esophageal nodose C-fibers in baseline and/or in sensitized state induced by inflammatory mediators. Ex vivo extracellular recordings were made from the esophageal nodose C-fibers in the isolated vagally-innervated guinea pig esophagus. We found that the selective GABAB agonist baclofen (100- 300 μM) did not inhibit activation of esophageal nodose C-fibers evoked by esophageal distention (10-60 mmHg). The mechanical response of esophageal nodose C-fibers can be sensitized by different pathways including the stimulation of the histamine H1 receptor and the stimulation the adenosine A2A receptor. Baclofen failed to inhibit mechanical sensitization of esophageal nodose Cfibers induced by histamine (100 μM) or the selective adenosine A2A receptor agonist CGS21680 (3 nM). Our data suggest that the direct mechanical inhibition of nodose C-fibers in the esophagus is unlikely to contribute to beneficial effects of GABAB agonists in patients with esophageal diseases., M. Brozmanová, ... [et al.]., and Obsahuje seznam literatury
We studied the effects of GABA receptor agonists microinjections
in medullary raphé on the mechanically induced tracheobronchial
cough response in anesthetized, unparalyzed, spontaneously
breathing cats. The results suggest that GABA-ergic inhibition
significantly contributes to the regulation of cough reflex by
action of both GABAA and GABAB receptors. The data are
consistent with inhomogeneous occurrence of GABA-ergic
neurons in medullary raphé and their different involvement in the
cough reflex control. Cells within rostral nucleus raphé obscurus
with dominant role of GABAA receptors and neurons of rostral
nucleus raphé pallidus and caudal nucleus raphé magnus with
dominant role of GABAB receptors participate in regulation of
cough expiratory efforts. These cough control elements are
distinct from cough gating mechanism. GABA-ergic inhibition in
the raphé caudal to obex had insignificant effect on cough.
Contradictory findings for GABA, muscimol and baclofen
administration in medullary raphé suggest involvement of
coordinated activity of GABA on multiple receptors affecting
raphé neurons and/or the local neuronal circuits in the raphé
modulating cough motor drive.
Our data indicate the significant intrinsic efficacy of GABABreceptors in rat brain cortex already at birth (PD1, PD2). Subsequently, baclofen- and SKF97541-stimulated G-protein activity, measured by agonist-stimulated, high-affinity [35S]GTPγS binding assay, was increased; the highest level of both baclofen and SKF97541-stimulated [35S]GTPγS binding was detected between PD10 and PD15. In older rats, baclofen- and SKF97541- stimulated [35S]GTPγS binding was continuously decreased so, that the level in adult, 90-days old animals, was not different from that in newborn animals. The potency of G-protein response to baclofen (characterized by EC50 values) was also high at birth but unchanged by further postnatal development. An individual variance among different agonists was observed in this respect as the potency of SKF97541 response was decreased between the birth and adulthood. Accordingly, the highest plasma membrane density of GABAB-R, determined by saturation binding assay with antagonist [3 H]CGP54626, was measured in 1-day old animals (2.27±0.08 pmol · mg-1). The further development was reflected in a decrease of [3 H]CGP54626 binding as the Bmax values of 1.38±0.05 and 0.93±0.04 pmol · mg-1 were determined in PM isolated from 13- and 90-days old rats, respectively., D. Kagan, ... [et al.]., and Obsahuje seznam literatury