Real-time dynamics of nitric oxide shifts within the esophageal wall
ABSTRACT Currently, indirect evidence suggests that the neurotransmitter nitric oxide (NO) plays a crucial role in the genesis of aboral propagation of esophageal peristalses during swallowing. However, direct evidence in this regard currently is lacking. This study aimed to assess the feasibility of using NO-selective microprobes to detect real-time NO changes within the esophageal wall of North American opossums (Didelphis virginiana) during normal progressive esophageal peristalsis and induced esophageal dysmotility.
Six adult opossums of both sexes (mean weight, 2.28 +/- 0.41 kg) were included in the study. All had normal esophageal motility, as documented by water-perfused esophageal manometry. A calibrated carbon fiber NO-selective microelectrode (ISNOP30, ISNOP100) was placed within the smooth muscle portion of the esophageal wall, and changes in NO levels were measured as redox current in pico-amperes (pA) with the Apollo-4000 NO meter. The dynamics of NO in response to reflexive deglutition were assessed during both normal propagative peristalsis and abnormal esophageal contractions induced by intravenous (i.v.) administration of the neural NO synthase inhibitor L-nitro L-arginine methyl ester (L-NAME) and banding of the gastroesophageal junction (GEJ) for 4-weeks.
During normal propagative esophageal peristalsis, a mean change of 2,158.85 +/- 715.93 pA was measured by the NO meter. Intravenous administration of L-NAME and chronic banding of the GEJ induced achalasia-like esophageal contractions. A significantly smaller change in levels of NO was detected within the esophageal wall during dysfunctional motility (331.94 +/- 188.17 pA; p < 0.001) than during normal propagative peristalsis (579 +/- 385 pA; p < 0.001).
The results of this study indicate that carbon fiber NO-selective microprobes can successfully measure changes in the concentration of NO, an important inhibitory neurotransmitter, within the esophageal wall and that these preliminary data support the involvement of this crucial neurotransmitter in programming normal propagation of peristaltic waves within the esophagus.
- [Show abstract] [Hide abstract]
ABSTRACT: Esophageal peristalsis generally does not return to normal after surgical treatment of achalasia. Direct electrical stimulation of the vagus nerve is known to stimulate antegrade peristalsis in the normal esophagus; however, it is not known whether electrical stimulation will induce return of peristalsis once an achalasia-like disorder has been established. The objective of this study was to perform quantitive and qualitative measurements of motility during electrical stimulation of the vagal nerve in an animal model of achalasia. An already established and verified animal achalasia model using adult North American opossums (Didelphis virginiana) was used. Fifteen opossums were divided into three groups. Sham surgery was performed on three animals (group 1). In group 2 (n=6) a loose Gore-Tex band (110% of the esophageal circumference) was placed around the gastroesophageal junction to prevent relaxation of the lower esophageal sphincter during swallowing. In group 3 (n=6) a relatively tighter band (90% of the esophageal circumference) was used to further elevate the lower esophageal sphincter pressure. At 6 weeks, after manometric and radiolologic confirmation of achalasia, electrical stimulation of the esophagus was performed before and after removal of the band using a graduated square-wave electrical stimulus. Changes in esophageal neural plexi were assessed histologically. Pre- and postoperative manometric data were compared using standard statistical techniques. No difference was observed in esophageal characteristics and motility after sham surgery in group 1. Animals in group 2 demonstrated a vigorous variety of achalasia (high-amplitude, simultaneous, repetitive contractions), moderate esophageal dilatation, and degeneration of 40% to 60% of intramuscular nerve plexi. Animals in group 3 developed amotile achalasia with typical low-amplitude simultaneous (mirror image) contractions, severely dilated ("bird beak") esophagus, and degeneration of 50% to 65% of nerve plexi. Vagal stimulation in group 2 demonstrated a significant increase in the amplitude of contractions (P<0.001) and return of peristaltic activity in 49% of swallows before band removal. After band removal, all of the contractions were peristaltic. In group 3 vagal stimulation before and after removal of the band demonstrated a significant increase in amplitude of contractions (P<0.0001) but no return of propagative peristalsis before band removal, however, 44% of contractions were progressive in the smooth portion of the esophagus after removal of the band. Electrical stimulation of the vagus nerve improved the force of esophageal contractions irrespective of the severity of the disease; however, peristaltic activity completely returned to normal only in the vigorous (early) variety of achalasia. Removal of the functional esophageal outlet obstruction, as with a surgical myotomy, may be necessary to obtain significant peristalsis with vagal pacing in severe achalasia.Journal of Gastrointestinal Surgery 11/2003; 7(7):843-9; discussion 849. DOI:10.1007/s11605-003-0028-6 · 2.39 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The influence of two successive vagal stimuli on esophageal contractions was studied by recording intraluminal pressures in the smooth muscle portion of the opossum esophagus. The esophageal contraction in response to the first or second stimulus in a pair of vagal stimuli was inhibited depending on the interstimulus interval, the frequency of the stimulus, and the esophageal site. The esophageal contraction in response to the first vagal stimulus was inhibited by a second vagal stimulus if the latter stimulus was applied before the peak of the first contraction. This phenomenon is termed initial inhibition. Initial inhibition is a graded phenomenon. It was greater at higher frequencies than at lower frequencies (p less than 0.001), and was significantly greater in the distal esophagus than in the proximal esophagus (p less than 0.01). The term "refractoriness" has been used to denote inhibition of the second esophageal contraction by the first. Refractoriness was observed during and beyond the duration of the first esophageal response. Refractoriness was also observed at all esophageal levels; however, the interstimulus intervals that demonstrated refractoriness were significantly greater in the distal than in the proximal esophagus (p less than 0.01). Refractoriness was complete (effective refractory period) during the ascending phase of the first contraction. Refractoriness was incomplete after the peak of the contraction (relative refractory period). These studies show gradients of durations and degrees of initial inhibition and refractoriness along the esophagus. The gradient is responsible for the peristaltic nature of esophageal contraction. The gradients of initial inhibition and refractoriness determine esophageal response to multiple successive swallows.Gastroenterology 11/1985; 89(4):843-51. · 13.93 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Nitric oxide controls lower esophageal sphincter (LES) relaxation and esophageal peristalsis in opossums, but its role in the control of esophageal motility in humans is not defined. Hemoglobin inactivates NO by binding it. Recombinant human hemoglobin (rHb1.1) was used to test the hypothesis that NO mediates esophageal motor functions in humans. rHb1.1 or human serum albumin was administered intravenously to fasting male volunteers. Esophageal manometric studies were performed before, during, and up to 6 hours after the infusion. rHb1.1 increased the velocities of peristaltic contractions to produce simultaneous contractions in 6 of 9 subjects. It increased the amplitude and duration of contractile waves in the esophagus. There was no consistent effect on the resting tone of the LES, but LES relaxation was inhibited. Spontaneous, simultaneous high-pressure contractions occurred in 8 of 9 subjects. Lower retrosternal chest pain during swallowing was observed in 4 subjects. rHb1.1 interfered with esophageal peristalsis and LES relaxation. It precipitated esophageal spasm in some subjects. These data support the hypothesis that the timing of smooth muscle esophageal peristalsis and LES relaxation are mediated by NO. They suggest that some disorders of esophageal motor function may result from defects in NO neuromuscular communication.Gastroenterology 10/1995; 109(4):1241-8. · 13.93 Impact Factor