| Summary: | 博士 === 國立臺灣大學 === 生理學研究所 === 97 === The occurrence and severity of gastroesophageal reflux disease (GERD) is determined by the balance between the aggressive factor, e.g. acid, and the protective factors, e.g. gastroesophageal junction barrier, esophageal mechanical clearance (peristalsis), and esophageal epithelial functions. We have conducted a series of experiments in the aspects of neurophysiological mechanisms of GERD, including the ion fluxes in the esophageal epithelium, the neuromuscular activities of lower esophageal sphincter (LES) in response to acid, and the potential effect of electroacupuncture (Ea) on the esophageal motility.
We investigated the mechanism of enhanced ion fluxes in response to luminal hydrochloric acid challenge in esophageal stratified squamous epithelium using an ex vivo rat model. The results showed that rat esophageal tissues devoid of submucosal glands displayed basal short-circuit current (Isc) of 5.03 ± 1.93 μA/cm2 and lumen-negative potential difference (PD) in association with net absorption of Na+ and Cl-, and secretion of HCO3-. Luminal hydrochloric acid (HCl) challenge (pH=1.6) triggered an acute rise of the Isc and increment of negative PD to seven-fold of baseline, which was diminished in HCO3--free, but not Na+- free buffer. The rise of Isc was inhibited by pretreatment with di-isothiocyanatostilbene-2, 2''-disulphonic acid (DIDS) and 5-(N-ethyl-N-isopropyl)-amiloride (EIPA). Topical carbachol, capsaicin, forskolin or CFTRinh-172 had no effect on basal Isc. CFTRinh-172 did not reduce the acid-increased Isc. Functional ablation of capsaicin-sensitive nerves had no effect on the acid-induced Isc. The phenomenon of enhanced ion fluxes upon acid stimulation was confirmed in human esophageal specimens. It is concluded that the mechanism of acid-induced rapid transepithelial ion fluxes is dependent on the presence of bicarbonate ions as well as functional anion transporters and Na+/H+ exchanger, but independent of cystic fibrosis transmembrane conductance regulator (CFTR). The capsaicin-sensitive and muscarinic-dependent nerve pathways did not play roles in the mechanism.
In our preliminary data in the in vitro LES muscle strip, LESP was amplified by acid (1.2 N, 50 ~ 250 μL) stimulation in a dose dependent response. We further evaluated esophageal vagus nerve activity (EVNA) and lower esophageal sphincter pressure (LESP) simultaneously by intra-esophageal acid (0.1 N hydrochloric acid) challenge to LES zone in rats. The results showed that in vivo rats, there were three patterns of amplified neuromuscular activity of LES upon acute acid challenge: (1) increased amplitude and duration of phasic LES contraction and EVNA; (2) bigeminy of amplified phasic LES contraction and EVNA; (3) exaggerated LESP and EVNA, characterzied with superimposed phasic LES contractions and clustered amplification of EVNA. The amplitude and frequency of LES contractile activity were attenuated by intravenous atropine and α,β-methylene ATP in both resting and acid-stimulated status. It is concluded that acute acid stimulation to esophagus may amplify vagus nerve-mediated LES contractile activity via purinergic and cholinergic pathways.
We evaluated the effects and underlying mechanisms of electroacupuncture (Ea) stimulation on intraluminal esophageal pressure (IEP) in anesthetized rats. Ea stimulation (intensity of 20 times of motor threshold and pulse duration of 0.05ms) at Hoku acupoint (Li 4) of right forlimb was tested by a low frequency (2 Hz; LFEa) and a high frequency (20 Hz; HFEa) with total stimulation time of 10 minutes. The results showed that pressor effects on esophageal body (IEP) and blood vessels (BP) were elicited by LFEa and the HFEa. Bilateral cervical vagotomy completely abolished both the LFEa- and HFEa-induced pressor response on IEP, while the pressor effects on BP were not affected. Ipsilateral brachial nerve plexus transaction after bilateral cervical vagotomy completely abolished the LFEa- and HFEa-induced pressor response on IEP and BP. It is concluded that Ea stimulation at Li 4 can simultaneously modulate dual physiological response in blood vessels and esophageal body via different somato-autonomic reflex pathways.
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