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Pyloric electrical stimulation reduces food intake by inhibiting gastric motility in dogs

2005; Elsevier BV; Volume: 128; Issue: 1 Linguagem: Inglês

10.1053/j.gastro.2004.09.079

1528-0012

Xiaohong Xu, Hongbing Zhu, Jiande D. Z. Chen,

Infant Health and Development

Background & Aims: The pylorus plays an important role in regulating gastric emptying. The aim of this study was to investigate the therapeutic potential of pyloric electrical stimulation (PES) for obesity in dogs. Methods: The study was composed of 3 separate experiments. The first experiment was designed to study the effects of PES with various parameters on gastric emptying and gastric slow waves in 5 sessions. The second experiment was used to test the effects of PES on antral contractions. The acute effect of PES on food intake was studied in the third experiment. Results: (1) Pyloric myoelectrical recording showed dual frequencies. The lower frequency was identical to the frequency of the gastric slow waves, and the higher frequency was similar to that of the intestinal slow waves. (2) Gastric emptying was significantly delayed with PES, and the delay in gastric emptying was significantly and negatively correlated with stimulation energy (r = −.673; P < .001). (3) PES significantly impaired the regularity and coupling of the intrinsic gastric myoelectrical activity in an energy-dependent manner. The delayed gastric emptying was significantly correlated with the impairment of the coupling of gastric myoelectrical activity (r = .441; P < .02). (4) Antral contractions on the fed state were significantly and substantially inhibited with PES. (5) Acute PES significantly reduced food intake. Conclusions: PES reduces food intake that may be attributed to its inhibitory effects on intrinsic gastric myoelectrical activity, antral contractions, and gastric emptying. Background & Aims: The pylorus plays an important role in regulating gastric emptying. The aim of this study was to investigate the therapeutic potential of pyloric electrical stimulation (PES) for obesity in dogs. Methods: The study was composed of 3 separate experiments. The first experiment was designed to study the effects of PES with various parameters on gastric emptying and gastric slow waves in 5 sessions. The second experiment was used to test the effects of PES on antral contractions. The acute effect of PES on food intake was studied in the third experiment. Results: (1) Pyloric myoelectrical recording showed dual frequencies. The lower frequency was identical to the frequency of the gastric slow waves, and the higher frequency was similar to that of the intestinal slow waves. (2) Gastric emptying was significantly delayed with PES, and the delay in gastric emptying was significantly and negatively correlated with stimulation energy (r = −.673; P < .001). (3) PES significantly impaired the regularity and coupling of the intrinsic gastric myoelectrical activity in an energy-dependent manner. The delayed gastric emptying was significantly correlated with the impairment of the coupling of gastric myoelectrical activity (r = .441; P < .02). (4) Antral contractions on the fed state were significantly and substantially inhibited with PES. (5) Acute PES significantly reduced food intake. Conclusions: PES reduces food intake that may be attributed to its inhibitory effects on intrinsic gastric myoelectrical activity, antral contractions, and gastric emptying. The prevalence of obesity is reaching an alarming rate worldwide. In the United States alone, there are approximately 300,000 deaths a year caused by obesity and more than $100 billion is spent each year for the treatment of obesity and its primary comorbidities.1Klein S. Obesity.Clin Perspect Gastroenterol. 2000; 3: 232-236Google Scholar, 2Martin L.F. Hunter S.M. Lauve R.M. O'Leary J.P. Severe obesity expensive to society, frustrating to treat, but important to confront.South Med J. 1995; 88: 895-902Crossref PubMed Scopus (89) Google Scholar, 3Colditz G.A. Economic costs of obesity.Am J Clin Nutr. 1992; 55: 503S-507SPubMed Scopus (326) Google Scholar, 4Wolf A.M. Colditz G.A. Current estimates of the economic cost of obesity in the United States.Obes Res. 1998; 6: 97-106Crossref PubMed Scopus (955) Google Scholar Globally, there are about 1.7 billion people who are overweight or obese and more than 2.5 million deaths are caused by obesity every year.5Professor Philip James, Chair of the London-based international obesity task force. Monte Carlo, March 17, 2003. Available at: www.iotf.org/media. Accessed March 1, 2004.Google Scholar, 6World Health Report 2002. Available at: www.iotf.org. Accessed March 1, 2004.Google Scholar Moreover, obesity leads to a high rate of disability, early retirement, and widespread discrimination and increased socioeconomic problems.7Enzi G. Socioeconomic consequences of obesity the effect of obesity on the individual.Pharmacoeconomics. 1994; 5: 54-57Crossref PubMed Scopus (27) Google Scholar Although various treatment options are available for obesity, such as diet, exercises, drugs, and surgery, there is an urgent need to develop safer and more effective methods to treat patients with morbid obesity, as concluded by a panel of experts at a National Institutes of Health consensus conference.8Consensus Development Conference PanelGastrointestinal surgery for severe obesity.Ann Intern Med. 1991; 15: 956-961Google Scholar Gastric electrical stimulation has received increasing attention among researchers and clinicians in recent years, and a number of studies have been performed to investigate the effect of gastric pacing on gastric motility.9McCallum R.W. Chen J.D.Z. Lin Z.Y. Schirmer B.D. Williams R.D. Ross R.A. Gastric pacing improves emptying and symptoms in patients with gastroparesis.Gastroenterology. 1998; 114: 456-461Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 10Lin Z.Y. McCallum R.W. Schirmer B.D. Chen J.D.Z. Effects of pacing parameters on entrainment of gastric waves in patients with gastroparesis.Am J Physiol. 1991; 274: G186-G191Google Scholar, 11Bellahsene B.E. Lind C.D. Schirmer B.D. Updike O.L. McCallum R.W. Acceleration of gastric emptying with electrical stimulation in a canine model of gastroparesis.Am J Physiol. 1992; 262: G826-G834PubMed Google Scholar, 12Qian L.W. Lin X.M. Chen J.D.Z. Normalization of atropine-induced postprandial dysrhythmias with gastric pacing.Am J Physiol. 1999; 276: G387-G392PubMed Google Scholar, 13Forster J. Sarosiek I. Delcore R. Lin Z.Y. Raju G.S. McCallum R.W. Gastric pacing is a new surgical treatment for gastroparesis.Am J Surg. 2001; 182: 676-681Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 14Eagon J.C. Kelly K.A. Effects of gastric pacing on canine gastric motility and emptying.Am J Physiol. 1993; 265: G767-G774PubMed Google Scholar, 15Miedema B.W. Sarr M.G. Kelly K.A. Pacing the human stomach.Surgery. 1992; 111: 143-150PubMed Google Scholar, 16Sarna S.K. Bowes K.L. Daniel E.E. Gastric pacemaker.Gastroenterology. 1976; 70: 226-231PubMed Scopus (87) Google Scholar, 17Xu X.H. Qian L.W. Chen J.D.Z. Anti-dysrhythmic effects of long-pulse gastric electrical stimulation in dogs.Digestion. 2004; 69: 63-70Crossref PubMed Scopus (23) Google Scholar Cigaina et al were the first to investigate the potential for gastric electrical stimulation to induce weight loss in a porcine model in 1992, and the study results showed that gastric electrical stimulation was safe and effective to inhibit weight gain and food intake in growing swine.18Cigaina V. Saggioro A. Rigo V. Pinato G. Ischai S. Long-term effects of gastric pacing to reduce feed intake in swine.Obes Surg. 1996; 6: 250-253Crossref PubMed Scopus (103) Google Scholar Recently, preliminary clinical studies by Cigaina et al showed that gastric electrical stimulation induced weight loss in morbidly obese patients.19Cigaina V. Gastric pacing as therapy for morbid obesity preliminary results.Obes Surg. 2002; 12: 12S-16SCrossref PubMed Google Scholar Shikora et al reported a multicenter, randomized, double-blinded clinical trial in which the safety and efficacy of a transcend implantable gastric stimulation system for weight loss was evaluated.20Shikora S.A. Bessier M. Fisher B.L. Trigillo C. Mincure M. Greenstein R. Laparoscopic insertion of the implantable gastric stimulator (IGSTM) initial surgical experience.Obes Surg. 2000; 10 (Appendix 3-A)Google Scholar While in the simplest term, obesity is known to be attributed to an imbalance between food intake and energy expenditure, the exact etiologies are not well understood. A number of basic and clinical studies have suggested that accelerated gastric emptying may also play a role in obesity. Duggan and Booth reported that rapid gastric emptying is the major primary cause of the obesity resulting from ventromedial hypothalamic lesions in rats and suggested that therapy for obesity could include slowing of stomach emptying.21Duggan J.P. Booth D.A. Obesity, overeating, and rapid gastric emptying in rats with ventromedial hypothalamic lesions.Science. 1986; 231: 609-611Crossref PubMed Scopus (97) Google Scholar In patients with obesity, rapid gastric emptying has been frequently reported.22Wright R.A. Krinsky S. Fleeman C. Trujillo J. Teague E. Gastric emptying and obesity.Gastroenterology. 1983; 84: 747-751PubMed Scopus (212) Google Scholar In a study of 77 subjects (46 obese and 31 age-, sex-, and race-matched nonobese individuals), obese subjects were found to have a more rapid emptying rate than nonobese subjects.22Wright R.A. Krinsky S. Fleeman C. Trujillo J. Teague E. Gastric emptying and obesity.Gastroenterology. 1983; 84: 747-751PubMed Scopus (212) Google Scholar The pyloric sphincter is one of the most important factors in regulating gastric emptying.23Haba T. Sarna S.K. Regulation of gastroduodenal emptying of solids by gastropyloroduodenal contractions.Am J Physiol. 1993; 264: G261-G271PubMed Google Scholar, 24Bayguinov O. Sanders K.M. Role of nitric oxide as an inhibitory neurotransmitter in the canine pyloric sphincter.Am J Physiol. 1993; 264: G975-G983PubMed Google Scholar Gastric emptying results from the coordinated activity of the stomach, pylorus, and duodenum, that is, contractions or peristalsis in the stomach, relaxation of the pylorus, and readiness of the duodenum to receive the emptied chyme from the stomach. In this study, we proposed to electrically stimulate the pylorus at a pathologic frequency. It was hypothesized that pyloric electrical stimulation (PES) would impair intrinsic gastric myoelectrical activity and inhibit gastric contractions, thus delaying gastric emptying. All of these inhibitory effects would lead to a reduction in food intake. The aim of this study was to test these hypotheses in dogs. A total of 14 healthy female dogs (16–24 kg) were used in 3 separate experiments. After an overnight fast, anesthesia was induced with pentothal (11 mg/kg sodium thiopental intravenously; Abbott Laboratories, North Chicago, IL) and maintained on IsoFlo (2%–4% isoflurane, inhalation anesthesia; Abbott Laboratories) in oxygen (1 L/min) carrier gases delivered from a ventilator after endotracheal intubation. The dog was monitored via a pulse oximeter. Four pairs of 28-gauge cardiac pacing wires (A&E Medical, Farmingdale, NJ) were implanted on the gastric serosa along the great curvature at an interval of 4 cm with the most distal pair 2 cm above the pylorus. One pair of wires was implanted in the pylorus, and one pair of wires was implanted in the small intestinal serosa 10 cm below the pylorus. The location of the pylorus was determined by palpation by the surgeon at the location of anatomic junction of the stomach and proximal small intestine. The 2 electrodes in each pair were arranged in the circumferential pattern with a distance of about .5–1.0 cm. The electrodes were penetrated into the subserosal layer and were affixed to the serosa by nonabsorbable sutures. The connecting wires of the electrodes were tunneled through the anterior abdominal wall subcutaneously along the right side of the trunk and placed outside the skin around the right hypochondrium for the attachment to the recorder or the stimulator (World Precision Instruments, Sarasota, FL). In 6 dogs, a cannula was placed in the duodenum, 20 cm beyond the pylorus, for the assessment of gastric emptying. In 8 dogs, a gastric cannula instead of a duodenum cannula was placed 10 cm above the pylorus for the assessment of antral motility. The dog was transferred to a recovery cage after receiving medications for postoperative pain control. The study was initiated after the dogs were completely recovered from the surgery (usually 2 weeks after the surgery). The study was approved by the institutional animal care and use committees of the University of Texas Medical Branch at Galveston and performed at the University of Texas Medical Branch. The study was composed of 3 separate experiments. The study was initiated 2 weeks after the dogs were completely recovered from the surgery. The first experiment was performed in 6 dogs to study the effects of PES on gastric emptying and gastric slow waves. Each dog was studied in 5 randomized sessions (A-E) on 5 different days with different stimulation parameters: A (control): no stimulation; B: 10 cycles/min (stimulation frequency), .2 milliseconds (pulse width), 5 mA (pulse amplitude, constant current mode); C: 10 cycles/min, 50 milliseconds, 5 mA; D: 30 cycles/min, 50 milliseconds, 5 mA; and E: 30 cycles/min, 50 milliseconds, 10 mA. After an overnight fast, the dog was brought to the laboratory for the study. During each study session, a baseline recording was first made for 30 minutes in the fasting state. The recordings included 4-channel gastric, one-channel pyloric, and one-channel intestinal myoelectrical activity. After the baseline recording, a small balloon was placed into the small intestine 5 cm distal to the duodenal cannula and inflated with 10 mL of air to block distal flow of gastric effluent. The animal was then fed with 237 mL liquid meal (240 kcal; total fat, 4.0 g; total carbohydrate, 41.0 g; protein, 10.0 g; Boost; Mead Johnson Nutritionals, Evansville, IN), and no stimulation (A) or PES with one set of parameters (B-E) was initiated immediately after feeding and continued for 2 hours; gastric effluent was collected from the cannula every 15 minutes for 120 minutes. Postprandial gastric myoelectrical activities and intestinal myoelectrical activities were recorded for 2 hours simultaneously with the collection of gastric effluent. The second experiment was performed in 8 dogs to study the effects of PES on antral contractions. It consisted of 30 minutes of baseline, 30 minutes of PES, and 30 minutes of recovery. PES was performed using stimulation parameters known to delay gastric emptying and impair gastric slow waves based on the first experiment: 30 cycles/min, 50 milliseconds, and 10 mA. At the beginning of the study, each dog was fed with one can of solid dog food (413 kcal; 13.2 oz; crude protein, 8.0%; crude fat, 6.0%; crude fiber, 1.5%; moisture, 78.0%; Pedigree; Kal Kan Foods Inc, Vernon, CA) and a water-perfused manometric catheter (1 cm staggered catheter) was inserted via the gastric cannula to the distal stomach. The third experiment was performed in 5 of 8 dogs used in experiment 2 to investigate the effect of PES on acute food intake. It consisted of 2 sessions in a randomized order: PES session and control session (no stimulation). PES was performed using parameter set D in experiment 1 (30 cycles/min, 50 milliseconds, 5 mA). The study was performed in the regular canine cage where the dogs had been housed. The dog was fed exactly 28 hours before the study and then deprived of food for 28 hours until the experiment. A portable stimulator (Transneuronix Inc, Mt Arlington, NJ) was fixed at the back of the dog with the pylorus electrodes connected. PES (the portable stimulator was on) or sham stimulation (the portable stimulator was attached but turned off) was initiated; 30 minutes later, 2 kg (more than any dog could possibly consume) of regular solid food (gross energy, 4.33 kcal/g; calories provided by 27.8% protein, 23.3% fat [ether extract], and 49.0% carbohydrates; Labdiet, PMI Nutrition International, LLC, Brentwood, MO) was offered to the canine for 90 minutes in the cage. The stimulator was on or off (in the control session) during the entire experiment. No investigators were present in the cage to avoid any possible disturbance. At the end of the experiment, the leftover food was removed and weighed. The two sessions occurred at least 3 days apart. The liquid test meal (a can of Boost, 237 mL, 240 kcal) was evenly mixed with 100 mg of phenol red, and gastric emptying was determined by the assessment of the amount of phenol red in each collection obtained from the duodenal cannula. For each collection of the gastric effluent, the volume was recorded and a sample of 5 mL was taken and stored in a freezer. The samples were analyzed all together at the end of the study using a spectrophotometer. Gastric emptying was assessed by computing the amount of phenol red recovered from each collection of the gastric effluent. Gastric, pyloric, and intestinal myoelectrical activities were recorded from the 4 pairs of gastric serosal electrodes, one pair of pyloric electrodes, and one pair of intestinal electrodes using a multichannel recorder (Acknowledge III, EOG 100A; Biopac Systems, Inc, Santa Barbara, CA) with a cutoff frequency of 35 Hz. All signals were displayed on a computer monitor, digitized at a frequency of 100 Hz, and saved on the hard disk by an IBM-compatible 486 PC. For the spectral analysis of the gastrointestinal and pyloric slow waves, the recorded myoelectrical signal was filtered by a digital low-pass filter with a cutoff frequency of 1 Hz and down-sampled at 2 Hz. Gastric myoelectrical activity is composed of rhythmic slow waves with a frequency of 4–6 cycles/min and spikes with a frequency of about 2–10 Hz. The recorded signal after low-pass filter (a cutoff frequency of 1 Hz) was composed of only slow waves as spikes were filtered out. The following parameters were derived from the spectral analyses of the myoelectrical recordings. This parameter reflects the regularity of gastrointestinal slow waves and was computed using the adaptive running spectral analysis method.25Chen J.D.Z. McCallum R.W. Electrogastrographic parameters and their clinical significance.in: Chen J.D.Z. McCallum R.W. The electrogastrography principles and clinical applications. Raven, New York1994: 45-73Google Scholar In this method, the gastrointestinal myoelectrical recording was divided into 1-minute segments and the power spectrum of each 1-minute recording was derived using the previously validated adaptive spectral analysis method.25Chen J.D.Z. McCallum R.W. Electrogastrographic parameters and their clinical significance.in: Chen J.D.Z. McCallum R.W. The electrogastrography principles and clinical applications. Raven, New York1994: 45-73Google Scholar, 26Chen J.D.Z. McCallum R.W. Clinical applications of electrogastrography.Am J Gastroenterol. 1993; 88: 1324-1336PubMed Google Scholar The 1-minute segment of the recording was defined as normal if its power spectrum had a clear peak in the 4–6 cycles/min frequency range (stomach) or 17–22 cycles/min frequency range (small bowel). Otherwise, it was defined as abnormal. The percentage of normal slow waves was determined by computing the ratio between the number of normal segments and the total number of segments. The definition of the normal frequency range of 4–6 cycles/min was based on our previous study,27Xu X.H. Wang Z.S. Hayes J. Chen J.D.Z. Is there a one-to-one correlation between gastric emptying of liquids and gastric myoelectrical or motor activity in dogs?.Dig Dis Sci. 2002; 47: 365-372Crossref PubMed Scopus (25) Google Scholar and the definition of the intestinal normal slow wave frequency range of 17–22 cycles/min was based on another previous study.28Lin X. Peters L.J. Hayes J. Chen J.D. Entrainment of segmental small intestinal slow waves with electrical stimulation in dogs.Dig Dis Sci. 2000; 45: 652-656Crossref PubMed Scopus (51) Google Scholar The percentage of normal gastric slow waves presented in Results was an average among the 4 channels. A cross-spectral analysis method developed in our laboratory was used to calculate the percentage of slow wave coupling among the 4-channel recordings.29Lin X. Chen J.D.Z. Abnormal gastric slow waves in patients with functional dyspepsia assessed by multichannel electrogastrography.Am J Physiol. 2001; 280: G1370-G1375Google Scholar It was computed on a minute-by-minute basis. First, the adaptive running spectral analysis was performed on each channel minute by minute, and the dominant frequency of the slow wave in each minute of the recording was derived. The corresponding dominant frequencies of the slow wave between any 2 channels were then compared minute by minute. The minute of the slow wave recorded on the 2 channels was defined as coupled if their dominant frequencies were both within the normal frequency range and their difference was <.2 cycles/min. The percentage of slow wave coupling was defined as the ratio between the number of time segments during which the recorded slow waves were coupled and the total number of segments. The percentage presented in Results was an average among the 4 channels. Antral contractile activities were recorded from the 4 pressure sensors of 1 cm apart attached to the manometric catheter by using a PC polygraf HR system (Synectics Medical, Stockholm, Sweden) and a microcapillary infusion system (model 8; Medtronic Synectic, Stockholm, Sweden). All recordings were displayed on a computer monitor. A parameter, called the area under the curve, was used to represent the contractile strength of the distal stomach. It was defined as the area under each of the contractions and calculated using Polygram Function Testing software (Medtronic, version 2.04; Synectics Medical). The data presented in this study were obtained from channel 3, which was of the highest quality of the recording. Data were reported as mean ± SE. One-way analysis of variance (ANOVA) was used to compare the difference of each parameter among the 5 study sessions in experiment 1 and the difference among 3 periods in experiment 2. Paired t test was used to investigate the difference in each of these parameters between any 2 study sessions in experiment 1 or the difference between any 2 study periods in experiment 2 or the difference between the control session and the PES session in experiment 3. Spearman rank order correlation was used to study the correlation between any 2 parameters in experiment 1. The results were regarded as significant when the P value was <.05. Pyloric myoelectrical recording showed dual frequencies at 5.27 ± .08 cycles/min and 20.13 ± .17 cycles/min. The lower frequency was identical to the slow waves measured from the gastric electrodes (5.27 ± .09 cycles/min), and the percentage of 4–6 cycles/min slow wave was 85.06% ± 5.68% in the pyloric myoelectrical recording; the higher frequency was similar to that of the intestinal slow waves (19.94 ± .19 cycles/min), and the percentage of 17–22 cycles/min slow wave was 86.30% ± 9.08% in the pyloric myoelectrical recording (see Figure 1). PES significantly delayed gastric emptying (ANOVA; P < .001) but did not induce any remarkable symptoms in dogs. Gastric emptying in the 5 different sessions is presented in Figure 2. As shown, gastric emptying was delayed with PES in an energy-dependent manner; gastric emptying was significantly and negatively correlated with stimulation energy (r = −.673; P < .001; Figure 3). The delay in gastric emptying reached significance after 15 minutes of PES with parameter E and after 60 minutes of PES with parameter D. PES with parameters B and C did not result in any significant changes in gastric emptying at any time points.Figure 3Correlation between percentage of gastric emptying and stimulation energy. A significant negative correlation was present between gastric emptying and stimulation energy after 30 minutes of feeding (r = −.673; P < .001).View Large Image Figure ViewerDownload (PPT) PES significantly decreased the regularity of gastric slow waves. The percentage of normal slow waves during the 30-minute treatment period was 94.0% ± 1.3% for control, 88.9% ± 1.9% with PES-B, 87.3% ± 2.7% with PES-C, 54.5% ± 13.9% with PES-D, and 70.1% ± 5.2% with PES-E (P < .01; ANOVA). In comparison with the control (no stimulation), the gastric slow wave rhythmicity was significantly reduced with PES-D (P < .05) or PES-E (P < .05). PES had similar effects on the percentage of slow wave coupling. The percentage of slow wave coupling was 67.5% ± 4.5% for control, 64.0% ± 5.4% with PES-B, 49.0% ± 10.1% with PES-C, 26.8% ± 11.7% with PES-D (P < .005 vs control), and 25.9% ± 5.3% with PES-E (P < .007 vs control) (P < .005; ANOVA). There was a significant negative correlation between the gastric slow wave coupling and stimulation energy 30 minutes postprandially (r = −.632; P < .001). It was also found that the percentage of slow wave coupling was slightly but significantly correlated with gastric emptying at 30 minutes (r = .441; P < .02). PES significantly inhibited antral contractions, and the effect was sustained during the 30-minute recovery period without PES. The area under the curve was 16.38 ± 2.30 at baseline and decreased to 6.96 ± 1.49 (P < .0006 vs baseline) during PES and 5.53 ± 1.64 (P < .002 vs baseline) during the 30-minute recovery period (P < .01; ANOVA). Antral contractions were almost completely inhibited with PES in 4 dogs and partially inhibited in the other 4 dogs. Recording of antral contractions from one dog is shown in Figure 4. None of the 8 dogs showed any obvious symptoms during the entire experimental period. PES resulted in a 25% reduction in food intake. The amount of food intake was 392.8 ± 99.9 g with sham PES (control) and reduced to 296.2 ± 93.9 g with PES (P < .02). No noticeable symptoms were observed with PES. In this study, we found that PES with long pulses significantly delayed gastric emptying, impaired gastric myoelectrical activity, inhibited antral contraction, and reduced food intake without inducing any noticeable symptoms in dogs. Gastric electrical stimulation has received increasing attention among researchers and clinicians in recent years, and a number of studies have been performed to explore the effects of gastric pacing on gastric motility.9McCallum R.W. Chen J.D.Z. Lin Z.Y. Schirmer B.D. Williams R.D. Ross R.A. Gastric pacing improves emptying and symptoms in patients with gastroparesis.Gastroenterology. 1998; 114: 456-461Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 10Lin Z.Y. McCallum R.W. Schirmer B.D. Chen J.D.Z. Effects of pacing parameters on entrainment of gastric waves in patients with gastroparesis.Am J Physiol. 1991; 274: G186-G191Google Scholar, 11Bellahsene B.E. Lind C.D. Schirmer B.D. Updike O.L. McCallum R.W. Acceleration of gastric emptying with electrical stimulation in a canine model of gastroparesis.Am J Physiol. 1992; 262: G826-G834PubMed Google Scholar, 12Qian L.W. Lin X.M. Chen J.D.Z. Normalization of atropine-induced postprandial dysrhythmias with gastric pacing.Am J Physiol. 1999; 276: G387-G392PubMed Google Scholar, 13Forster J. Sarosiek I. Delcore R. Lin Z.Y. Raju G.S. McCallum R.W. Gastric pacing is a new surgical treatment for gastroparesis.Am J Surg. 2001; 182: 676-681Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 14Eagon J.C. Kelly K.A. Effects of gastric pacing on canine gastric motility and emptying.Am J Physiol. 1993; 265: G767-G774PubMed Google Scholar, 15Miedema B.W. Sarr M.G. Kelly K.A. Pacing the human stomach.Surgery. 1992; 111: 143-150PubMed Google Scholar, 16Sarna S.K. Bowes K.L. Daniel E.E. Gastric pacemaker.Gastroenterology. 1976; 70: 226-231PubMed Scopus (87) Google Scholar, 17Xu X.H. Qian L.W. Chen J.D.Z. Anti-dysrhythmic effects of long-pulse gastric electrical stimulation in dogs.Digestion. 2004; 69: 63-70Crossref PubMed Scopus (23) Google Scholar Over the past years, different methods of electrical stimulation have been derived from the variation of stimulation parameters, including long-pulse stimulation, short-pulse stimulation, and stimulation with train of pulses. Most previous studies explored therapeutic potentials for treating patients with motility disorders because electrical stimulation of the gut seemed capable of altering motor functions of the stomach or small intestine. Recently, gastric electrical stimulation has been under investigation for its potential for treating obesity. Promising preliminary clinical data have been obtained on its efficacy and safety in reducing weight in morbidly obese patients. In the method proposed by Cigaina et al, electrical stimulation was performed at the lesser curvature using trains of short pulses with a pulse width in the order of microseconds and pulse frequency of about 40 Hz (2400 cycles/min). Gastric electrical stimulation with a similar kind of short pulses has also been applied to treat patients with gastric motor disorder.13Forster J. Sarosiek I. Delcore R. Lin Z.Y. Raju G.S. McCallum R.W. Gastric pacing is a new surgical treatment for gastroparesis.Am J Surg. 2001; 182: 676-681Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 30The GEMS Study GroupElectrical stimulation for the treatment of gastroparesis—preliminary report of a multicenter international trial.Gastroenterology. 1996; 110 (abstr): A668Google Scholar, 31Abell T.L. Hocking M. McCallum R.W. Gastric electrical stimulation for gastroparesis a multi-center double blind cross over study, by the WAVESS Study Group.Gastroenterology. 2000; 118 (abstr): A393Google Scholar, 32Chen J.D.Z. Qian L.W. Ouyang H. Yin J.Y. Gastric electrical stimulation with short pulses improves vomiting but not gastric dysrhythmia in dogs.Gastroenterology. 2003; 124: 401-409Abstract Full Text PDF PubMed Scopus (158) Google Scholar The PES method proposed in this study was performed at the pylorus with a tachygastria frequency, a pulse width in the order of milliseconds. The nature of the stimulus (ie, long pulses with a width in the order of milliseconds) makes it possible for PES to more effectively alter the intrinsic gastric slow waves and motility, such as contractions and emptying. The location of the stimulation (pylorus) makes PES capable of impairing the normal distal propagation of the slow waves and peristalsis. Accordingly, PES was proposed to impair the intrinsic gastric slow waves by stimulation at a pathologic frequency of 10 cycles/min or 30 cycles/min (the normal frequency of the gastric slow wave in dogs is between 4 and 6 cycles/min). The impairment in gastric slow waves would lead to an inhibition in gastric contractions, yielding a delayed emptying of the stomach and a reduction in food intake. This novel concept has not been proposed or reported elsewhere. The experiments in this study were designed to test this concept. Firstly, we have shown that PES did impair the intrinsic myoelectrical activity. As in the heart, there is a pacemaker in the stomach. It is located in the midcorpus along the greater curvature. The gastric slow wave originates from the gastric pacemaker and propagates distally toward the pylorus. The normal frequency of the gastric slow wave is about 3 cycles/min in humans and 5 cycles/min in dogs. It determines the maximum frequency, propagation velocity, and propagation direction of gastric contractions. Because gastric motility is controlled by myoelectrical activity of the stomach, abnormalities in gastric myoelectrical activity may result in gastric motility disorders such as gastroparesis.33Chen J. McCallum R.W. Gastric slow wave abnormalities in patients with gastroparesis.Am J Gastroenterol. 1992; 87: 477-482PubMed Google Scholar Previous studies have shown that gastric electrical stimulation with long pulses at a frequency slightly higher than the intrinsic frequency of the gastric slow wave is able to pace the stomach to a slightly higher frequency or entrain the slow wave.10Lin Z.Y. McCallum R.W. Schirmer B.D. Chen J.D.Z. Effects of pacing parameters on entrainment of gastric waves in patients with gastroparesis.Am J Physiol. 1991; 274: G186-G191Google Scholar, 14Eagon J.C. Kelly K.A. Effects of gastric pacing on canine gastric motility and emptying.Am J Physiol. 1993; 265: G767-G774PubMed Google Scholar Such entrainment is of clinical significance because gastric dysrhythmia would then be normalized.12Qian L.W. Lin X.M. Chen J.D.Z. Normalization of atropine-induced postprandial dysrhythmias with gastric pacing.Am J Physiol. 1999; 276: G387-G392PubMed Google Scholar, 32Chen J.D.Z. Qian L.W. Ouyang H. Yin J.Y. Gastric electrical stimulation with short pulses improves vomiting but not gastric dysrhythmia in dogs.Gastroenterology. 2003; 124: 401-409Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 34Xu X.H. Chen J.D.Z. Effects of vasopressin and gastric electrical stimulation on gastric emptying, postprandial gastric and intestinal slow waves and symptoms in dogs.Gastroenterology. 2004; 126 (abstr): A490Google Scholar The aim of PES proposed in this study was just opposite; it was aimed at inducing gastric dysrhythmia or reducing the percentage of normal slow waves. Our findings have shown that PES at 30 cycles/min was capable of introducing a 30%–40% increase in gastric dysrhythmia or a 30%–40% decrease in normal slow waves. Simultaneously, there was a similar reduction in the percentage of slow wave coupling. The percentage of slow wave coupling represents the percentage of time during which the slow waves at various locations in the stomach were coordinated. A reduction in the value of this parameter reflects an impairment of slow wave propagation and thus a possible impairment in the propagation or coordination of antral contractions. In addition, a significant correlation was noted during PES between gastric emptying and slow wave coupling, suggesting that the PES-induced slow wave uncoupling was at least partially responsible for the delayed emptying of the stomach. Secondly, PES resulted in an inhibition of antral contractions. This finding was expected because the PES was performed using parameter E, which was effective in impairing gastric slow waves. Antral motility plays an important role in the regulation of gastric emptying. Malbert and Ruckebusch reported that the rate of abomasal outflow depended primarily on the strength of antral contractions.35Malbert C.H. Ruckebusch Y. Gastroduodenal motor activity associated with gastric emptying rate in sheep.J Physiol. 1988; 401: 227-239PubMed Google Scholar Houghton et al reported that solid emptying was associated with an increase in the rate of occurrence of antral pressure waves, and the half-time for solid emptying was inversely correlated with the rate of coordinated contractions involving the antrum.36Houghton L.A. Read N.W. Heddle R. Horowitz M. Collins P.J. Chatterton B. Dent J. Relationship of the motor activity of the antrum, pylorus, and duodenum to gastric emptying of a solid-liquid mixed meal.Gastroenterology. 1988; 94: 1285-1291Abstract PubMed Google Scholar Camilleri et al calculated motility index by using gastric manometry and reported a positive correlation of solid emptying with antral motility.37Camilleri M. Malagelada J.R. Brown M.L. Becker G. Zinsmeister A.R. Relation between antral motility and gastric emptying of solids and liquids in humans.Am J Physiol. 1985; 249: G580-G585PubMed Google Scholar Motility is one of the most critical physiologic functions of the human gut. Without coordinated motility, digestion and absorption of dietary nutrients cannot take place. To accomplish its functions effectively, the gut needs to generate not only simple contractions but also coordinated contractions (peristalsis). Coordinated gastric contractions are necessary for the emptying of the stomach. The inhibition in antral contractions observed in this study with PES is believed to be one of the major contributing factors in the delay of gastric emptying. Gastric emptying plays an important role in the regulation of food intake. Gastric emptying is reported to be accelerated in patients with obesity22Wright R.A. Krinsky S. Fleeman C. Trujillo J. Teague E. Gastric emptying and obesity.Gastroenterology. 1983; 84: 747-751PubMed Scopus (212) Google Scholar, 38Phillips R.J. Powley T.L. Gastric volume rather than nutrient content inhibits food intake.Am J Physiol. 1996; 271: R766-R779PubMed Google Scholar but delayed in patients with functional dyspepsia.39Quartero A.O. de Wit N.J. Lodder A.C. Disturbed solid-phase gastric emptying in functional dyspepsia. A meta-analysis.Dig Dis Sci. 1998; 43: 2028-2033Crossref PubMed Scopus (166) Google Scholar, 40Lorena S.L.S. Tinois E.M. Brunetto S.Q. Camargo E.E. Mesquita M.A. Gastric emptying and intragastric distribution of a solid meal in functional dyspepsia influence of gender and anxiety.J Clin Gastroenterol. 2004; 38: 230-236Crossref PubMed Scopus (60) Google Scholar As mentioned previously, the novel concept of the PES method proposed in this study was to delay gastric emptying. As expected, gastric emptying was indeed significantly delayed with PES at a frequency of 30 cycles/min. An increase in stimulation strength increases the potency of PES in delaying gastric emptying. The findings in this study strongly suggest that the delayed gastric emptying induced by PES was attributed to the impairment in the intrinsic gastric slow waves (a reduction in both regularity and coupling of slow waves) and inhibition of antral contractions. It is unknown, however, whether the pyloric pressure or motility was altered with PES. This was not investigated in the current study due to technical limitations. Last, but most importantly, food intake was reduced with PES. Although long-term clinical studies are required to confirm the therapeutic potential of PES for obesity, the findings in this study were encouraging. This is because (1) the reduction in food intake was substantial (a 25% decrease), (2) the concept of PES involving gastric myoelectrical activity and motility was well developed and proven in this study, (3) no noticeable symptoms were observed in the experiments and the animals tolerated PES well, and (4) the implementation of PES (placement of stimulation electrodes and implantable stimulator) can be achieved using a minimally invasive method of laparoscopy that has been proven safe.20Shikora S.A. Bessier M. Fisher B.L. Trigillo C. Mincure M. Greenstein R. Laparoscopic insertion of the implantable gastric stimulator (IGSTM) initial surgical experience.Obes Surg. 2000; 10 (Appendix 3-A)Google Scholar The disadvantage of this method is that we have to wait for the development of a new-generation implantable stimulator because no commercially available device is capable of delivering stimulation pulses with a width of more than 1 or 2 milliseconds. The limitation of this study was that the pyloric pressure was not measured. Antral, pyloric, and duodenal pressures can be simultaneously measured by a sleeve sensor and multiple perfused side holes.41Tracy P.J. Jamieson G.G. Dent J. Pyloric motor function during emptying of a liquid meal from the stomach in the conscious pig.J Physiol. 1990; 422: 523-538PubMed Google Scholar, 42Houghton L.A. Read N.W. Heddle R. Maddern G.J. Downton J. Toouli J. Dent J. Motor activity of the gastric antrum, pylorus, and duodenum under fasted conditions and after a liquid meal.Gastroenterology. 1988; 94: 1276-1284PubMed Google Scholar The sleeve sensor is used for recording pyloric manometry, whereas the side holes are used to record antral and duodenal pressures. The transpyloric sleeve sensor is positioned by continuously monitoring the transmucosal potential difference at the either side of the sleeve. The pyloric manometric recording is edited out if the 2-point transmucosal potential differences are out of range to guarantee that the sleeve sensor is positioned correctly in the pylorus. In conclusion, PES with long pulses at a frequency of about 30 cycles/min is capable of reducing food intake without inducing noticeable symptoms. The PESinduced reduction in food intake may be attributed to the inhibitory effects of PES on gastric myoelectrical activity and gastric contractions as well as gastric emptying. PES has a potential for the treatment of obesity, and further clinical studies are needed to prove its efficacy and safety.