Impact of perioperative chemotherapy on oncological outcomes after gastric cancer surgery.

BACKGROUND: Perioperative chemotherapy has become standard care for resectable gastric cancer. However, available evidence is based on a limited number of trials, and the outcomes in routine clinical practice and in unselected patients are scarcely reported. METHODS: The study included a consecutive series of patients with resectable gastric cancer treated between 2001 and 2011 in Central Norway. Before 2007, patients with resectable gastric cancer did not receive perioperative chemotherapy. Since 2007, medically fit patients with resectable gastric cancer and aged 75 years or less have been offered this. Response rates were evaluated by CT, and tolerability was assessed by the frequency of hospital admission, need for dose reduction or treatment discontinuation. The two time intervals were compared on an intention-to-treat basis for patients aged no more than 75 years for any impact on resection rates, surgical morbidity, postoperative mortality and long-term survival. RESULTS: About two-thirds (259) of the 419 patients registered were aged 75 years or less at diagnosis. Ninety-five of 136 patients in the later interval were eligible for chemotherapy, of whom 90 actually received the specified regimen, and 78 (87 per cent) were able to complete the preoperative course. Only 40 (44 per cent) completed all scheduled preoperative and postoperative cycles. Thirty-eight (43 per cent) of 89 evaluable patients showed a definite response on CT. Chemotherapy had no impact on postoperative morbidity or mortality. The 5-year survival rate on an intention-to-treat basis was 40·7 (95 per cent c.i. 30·7 to 50·7) per cent in the first interval, compared with 41·7 (31·5 to 51·9) per cent after the introduction of perioperative chemotherapy (P = 0·765). After adjustment for other risk factors, based on comparisons of the two time intervals, there were no differences in oncological outcomes with the use of perioperative chemotherapy. CONCLUSION: Perioperative chemotherapy was completed in less than half of the patients with resectable gastric cancer. An observed tumour response to chemotherapy did not translate into any long-term survival benefit compared with surgery alone.

Outcomes among patients treated for gastric adenocarcinoma during the last decade.

OBJECTIVES: To evaluate the outcomes among patients treated for gastric adenocarcinoma in a referral hospital, and to identify possible trends during the last decade. METHODS: All patients evaluated for gastric adenocarcinoma during the period 1999-2009 were included. RESULTS: Of 397 patients, 52% were curatively resected. Crude 5-year survival for the first 6 years period was 38.7% (CI 29.5-47.9), for the last 5 years, 49.2% (CI 38.8-59.6). Time period (P = 0.013), age (P < 0.001) and disease stage (P < 0.001), were significant predictors of long-term survival rates. Among curatively resected, in-hospital mortality was reduced from 8.5% in the first period to 2.0% in the last one (P = 0.037). There was a significant increase in the use of primary stents from the first to the last period (P = 0.006), paralleled by a significant reduction in the number of explorative laparotomies or bypass procedures (P < 0.001). CONCLUSIONS: During the last decade, long-term survival rates improved among patients curatively resected for gastric adenocarcinoma, and in-hospital mortality was substantially reduced. For patients in a non-curative situation, there was a significant shift from explorative laparotomies or bypass procedures to primary use of stents.

Regional distribution of blood flow during proximal aortic cross-clamping: an experimental study using coloured microspheres.

OBJECTIVE: To investigate the effect of thoracic aortic cross-clamping on blood perfusion of the brain, spinal cord, heart, muscular tissue and visceral organs. MATERIAL AND METHODS: Nine pigs underwent 30 min cross-clamping of the descending thoracic aorta. Multiple coloured microspheres (15.0 microm +/- 0.1) were infused into the left ventricle before and during aortic cross-clamping (XC) and after declamping (DC). Tissue samples were analysed by spectrophotometry. RESULTS: Blood perfusion of the middle and lower segments of the spinal cord was significantly reduced during aortic XC. Perfusion of the brain was not significantly altered by aortic XC, while perfusion of myocardium increased 3-fold. During XC, perfusion of the deltoid muscle and diaphragm increased 5-fold and 13-fold, respectively, while a decrease was found in the gluteus muscle. Renal blood flow was significantly reduced during XC. Finally, XC induced a significant decrease of perfusion in the bowel, spleen, liver and pancreas. CONCLUSION: During XC of the thoracic aorta, the perfusion of the muscular tissue was significantly increased proximal to the level of XC. The circulation of the brain was unchanged, probably because of autoregulatory mechanisms. Blood perfusion of the myocardium increased 3-fold during XC.

Lactate and glycerol released to the intestinal lumen reflect mucosal injury and permeability changes caused by strangulation obstruction.

BACKGROUND: The present study evaluates whether microdialysis of glycerol and lactate reflects mucosal injury and permeability changes after strangulation obstruction of the pig small intestine. METHODS: Strangulation obstruction was induced by tightening a rubber band around a small bowel loop until its venous pressure increased to a level just below diastolic aortic pressure (partial strangulation), or further until cessation of flow in the main feeding artery (total strangulation). Mucosal injury and permeability of marker molecules from blood to lumen and vice versa was compared to release of glycerol and lactate to the intestinal lumen. RESULTS: Mucosal injury, hyperpermeability, and release of glycerol were more pronounced after total than after partial strangulation. In animals with partial strangulation there was a complete restitution of the surface epithelium, and luminal glycerol and lumen-to-blood permeability of polyethylene glycol 4000 remained low. Such animals showed a sustained elevation of lactate and blood-to-lumen permeability of fluorescein isothiocyanate dextran after 2 h of partial strangulation, but a decline to baseline levels of these parameters in animals with 1 h partial strangulation. CONCLUSION: Microdialysis of lactate and glycerol in the intestinal lumen may be used to assess structural and functional changes of the intestinal mucosa after strangulation obstruction.

Rectal lactate levels in endoluminal microdialysate during routine coronary surgery.

The aim of this prospective study was to determine the feasibility of intestinal endoluminal microdialysis as a new method for clinical monitoring of the adequacy of splanchnic perfusion in the large bowel. A microdialysis catheter for continuous lactate, glycerol, glucose and pyruvate measurements attached to a tonometric catheter was placed into the lumen of the recto-sigmoid junction prior to surgery in 13 patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB). Lactate was also measured in blood and muscle. CPB was associated with a 10-fold increase in luminal lactate from 0.16 (0.01) to 1.67 (0.38) mmol x l(-1) (p < 0.001). Muscular lactate increased from baseline levels 1.20 (0.21) to 1.77 (0.36) mmol x l(-1) during CPB (p = 0.01), but the muscular lactate-pyruvate ratio remained unchanged. Arterial lactate increased only slightly from 0.9 (0.05) to 1.1 (0.06) mmol x l(-1) (p = 0.027) during CPB. Increased lactate concentrations in the large bowel during CPB are suggestive of local lactate production consistent with impaired oxygen delivery. Intestinal endoluminal microdialysis is a potential clinically applicable method for monitoring intestinal metabolism. Combined with tonometry, microdialysis provides the opportunity to monitor both circulation and metabolism in the rectal mucosa.

Hemodynamic and tissue blood flow responses to long-term pneumoperitoneum and hypercapnia in the pig.

BACKGROUND: Increased peritoneal blood flow may influence the ability of cancer cells to adhere to and survive on the peritoneal surface during and after laparoscopic cancer surgery. Carbon dioxide (CO2) pneumoperitoneum is associated with a marked blood flow increase in the peritoneum. However, it is not clear whether the vasodilatory effect in the peritoneum is related to a local or systemic effect of CO2. METHODS: In this study, 21 pigs were exposed to pneumoperitoneum produced with either CO2 (n = 7) or helium (He) (n = 7) insufflation at 10 mmHg for 4 h, or to two consecutive levels of hypercapnia (7 and 11 kPa) (n = 7) produced by the addition of CO2 to the inhalational gas mixture. Tissue blood flow measurements were performed using the colored microsphere technique. RESULTS: Blood flow in peritoneal tissue increased during CO2, but not He, pneumoperitoneum, whereas it did not change at any level of hypercapnia alone. There was no change in blood flow in most organs at the partial pressure of CO2 (PaCO2) level of 7 kPa. However, at a PaCO2 of 11 kPa, blood flow was increased in the central nervous system, myocardium, and some gastrointestinal organs. The blood flow decreased markedly in all striated muscular tissues during both levels of hypercapnia. CONCLUSION: The effect of CO2 on peritoneal blood flow during laparoscopic surgery is a local effect, and not attributable to central hemodynamic effects of CO2 pneumoperitoneum or high systemic levels of CO2.

ECL cell histamine mobilization and parietal cell stimulation in the rat stomach studied by microdialysis and electron microscopy.

AIM: Gastrin stimulates acid secretion by mobilizing histamine from enterochromaffin-like (ECL) cells that occur predominantly at the base of the gastric glands. The parietal cells occur higher up in the glands nearer to the gastric lumen. The present study was performed to assess whether histamine is transported from the ECL cell via the microcirculation (endocrine route) or local diffusion (paracrine route). METHODS: Totally isolated, vascularly perfused, rat stomachs were examined both in basal and gastrin-stimulated state. Histamine concentrations, determined by radioimmunoassay in venous effluent and microdialysate from an indwelling probe in the submucosa, were monitored over a period of 240 min. Gastrin-17 was infused through an arterial catheter for 120 min. The parietal cells were examined by electron microscopy, and the percentage of actively secreting parietal cells (displaying secretory canaliculi) in four regions along the glands (basal to surface, zones I-IV) was determined. RESULTS: Gastrin stimulated acid secretion and histamine release as well as parietal cell activation. Upon gastrin stimulation, histamine concentration in the microdialysate was 2.5-fold higher than in the venous effluent (P = 0.008). The parietal cells in the upper part of the gland (zone III) were found to be activated the most. CONCLUSION: As the histamine concentrations were higher in the tissue (microdialysate) than in blood, histamine seems to reach the parietal cells via the paracrine route. The fraction of active parietal cells seems to depend more on the age of the parietal cells than on the distance from the ECL cell.

Effect of carbon dioxide pneumoperitoneum on tissue blood flow in the peritoneum, rectus abdominis, and diaphragm muscles.

BACKGROUND: Changes in local blood flow may play a role in the pathogenesis of port-site metastasis. This study aimed to investigate the effect of pneumoperitoneum induced by carbon dioxide (CO2) on the blood flow in the peritoneum and abdominal wall muscle layers, which are target structures for this phenomenon. METHODS: The study was performed on domestic farm swine of both genders weighing 20 to 25 kg. Intraabdominal pressures (IAP) of 0, 5, and 10 mmHg were produced by either CO2 ( n = 9) or helium (He) ( n = 6) insufflations. The colored microsphere technique was used to measure blood flow distributions in the parietal peritoneum, rectus abdominis, and diaphragm muscles. RESULTS: Insufflation of CO2 was associated with a threefold increase in blood flow of the parietal peritoneum at both 5 and 10 mmHg IAP ( p < 0.001 for both pressure levels). In contrast, insufflation of He caused a significant decrease in blood flow in the parietal peritoneum at both 5 and 10 mmHg ( p < 0.05). In the rectus abdominis and diaphragm muscles, blood flow remained unchanged after insufflation of CO2 at both 5 and 10 mmHg IAP. However, after insufflation of He, there was a substantial decrease in blood flow both in the rectus abdominis and diaphragm muscles at both 5 mmHg ( p < 0.01 and p < 0.05, respectively) and 10 mmHg ( p < 0.001 and p < 0.01, respectively). CONCLUSIONS: Despite high intraabdominal pressure, tissues surrounding the abdominal cavity, particularly the peritoneum, respond to insufflation of CO2 with increased blood flow, which may favor the growth of tumor cells.

Mast cells are involved in the gastric hyperemic response to acid back diffusion via release of histamine.

Acid back diffusion into the rat stomach mucosa leads to gastric vasodilation. We hypothesized that histamine, if released from the rat mucosa under such conditions, is mast cell derived and involved in the vasodilator response. Gastric blood flow (GBF) and luminal histamine were measured in an ex vivo chamber. Venous histamine was measured from totally isolated stomachs. Mucosal mast cells (MMC), submucosal connective tissue mast cells (CTMC), and chromogranin A-immunoreactive cells (CgA IR) were assessed morphometrically. After mucosal exposure to 1.5 M NaCl, the mucosa was subjected to saline at pH 5.5 (control) or pH 1.0 (H(+) back diffusion) for 60 min. H(+) back diffusion evoked a marked gastric hyperemia, increase of luminal and venous histamine, and decreased numbers of MMC and CTMC. CgA IR cells were not influenced. Depletion of mast cells with dexamethasone abolished (and stabilization of mast cells with ketotifen attenuated) both hyperemia and histamine release in response to H(+) back diffusion. GBF responses to H(+) back diffusion were attenuated by H(1) and abolished by H(3) but not H(2) receptor blockers. Our data conform to the idea that mast cells are involved in the gastric hyperemic response to acid back diffusion via release of histamine.

Effect of increased intraabdominal pressure on cardiac output and tissue blood flow assessed by color-labeled microspheres in the pig.

BACKGROUND: Studies of the hemodynamic effects associated with the pneumoperitoneum have had controversial results. We set out to investigate the effect of increased intraabdominal pressure (IAP) on cardiac output and tissue blood flow in various intraabdominal and extraabdominal organs using the color-labeled microsphere (CLM) technique. METHODS: IAP was induced by CO2 insufflation in anesthetized pigs; 0, 5, and 10 mmHg was used in the low-pressure group and 0, 15, and 24 mmHg in the high-pressure group. Tissue blood flow (ml.min-1.g-1) and cardiac output (CO) (ml/min) were determined by the CLM technique. RESULTS: CO decreased at IAP > or = 15 mmHg. Arterial PaCO2 and hydrogen ion concentration increased in response to all levels of IAP. Arterial PaO2, oxygen saturation, and bicarbonate ion concentration remained unchanged. Low IAP did not influence tissue blood flows in most of the organs. However, in the spleen, pancreas, esophagus, and gastric mucosal specimens, tissue blood flow was significantly decreased at 24 mmHg. CONCLUSION: The level of IAP used in current practice (10-12 mmHg) appears to be safe with regard to hemodynamic variables and tissues blood flow; however, higher levels may induce a decrease in cardiac output and tissue blood flow.

Oxyntic lesions may be provoked in the rat both by the process of acid secretion and also by gastric acidity.

BACKGROUND: Gastric ischaemia appears to be a common pathogenetic factor for stress ulcers. These ulcers occur predominantly in the oxyntic mucosa, suggesting that the acid secretory process or its stimulation is involved in the pathogenesis. METHODS: We examined separately the role of the acid secretory process and gastric luminal acidity in the pathogenesis of gastric lesions using the isolated vascularly perfused acid-secreting rat stomach. RESULTS: Pentagastrin-stimulated acid secretion induced submucosal bleeding in the oxyntic mucosa whether accompanied by perfusion of the gastric lumen with saline or a phosphate buffer at pH 7.0. On the other hand, acidity, whether endogenous or introduced by luminal perfusion, induced erosions in both the oxyntic and antral mucosa. CONCLUSION: It is concluded that the acid secretory process itself contributes to the particular vulnerability of the oxyntic mucosa to ischaemia. Histamine released upon stimulation of gastric acid secretion or shortage of energy due to the requirements for acid secretion may both contribute to this vulnerability. Furthermore, these findings suggest that inhibition of gastric acid secretion should be superior to antacids in preventing stress ulcers.

Substance P may attenuate gastric hyperemia by a mast cell-dependent mechanism in the damaged gastric mucosa.

Calcitonin gene-related peptide (CGRP) released from sensory neurons, which are closely apposed to mast cells and blood vessels, mediates gastric hyperemia in response to acid challenge of the damaged mucosa. Substance P (SP) is coreleased with CGRP from sensory neurons, but the role of this peptide in gastric blood flow regulation is largely unknown. Chambered rat stomachs were exposed to 1.5 M NaCl and acidic saline after treatment with SP, aprotinin (serine protease inhibitor), and the mast cell stabilizers ketotifen and sodium cromoglycate (SCG). Gastric hyperemia (measured with a laser Doppler flow velocimeter) after hypertonic injury and acid challenge was nearly abolished by SP. Aprotinin infused together with SP and pretreatment with ketotifen and SCG before SP restored the gastric hyperemia. Ketotifen and SCG inhibited mast cell degranulation in SP-treated rats. Preservation of gastric hyperemia was correlated with improved mucosal repair. These data suggest that impaired hyperemia by SP during acid challenge of the gastric mucosa may be mediated by a mast cell-dependent mechanism involving the release of proteases from mast cells.

Acute erosions of the gastric mucosa in burned rats: effect of sucralfate.

The effect of intragastric sucralfate on development of gastric erosions in burns was studied in 20 rats anaesthetised with midazolam/fentanyl/fluanisone. Gastric blood flow was measured by radioactive microspheres immediately before, and 20, 40, and 120 minutes after the rats had been burned. Significantly fewer erosions were found in the 10 rats treated with sucralfate (less than 2% of the gastric mucosal surface was affected) compared with the controls (16% of the mucosa affected). There was no difference in the rate of gastric blood flow in any part of the stomach between the rats treated with sucralfate and the controls. We conclude that sucralfate is effective in preventing gastric erosions in burned rats, but that other mechanisms of action than increase gastric blood flow are responsible for its protective effect.

Role of sensory afferent neurons in hypertonic damage and restitution of the rat gastric mucosa.

BACKGROUND & AIMS: Gastric mucosal hyperemia is a protective response mediated at least in part by the response of sensory afferent neurons to hydrogen ions. The aim of this study was to determine if other pathways to the hyperemic response are present and if these neurons have an effect exclusive of hyperemia on mucosal protection and repair. METHODS: Rat sensory afferent neurons were ablated by capsaicin treatment. Chambered stomachs were damaged by hypertonic saline followed by either acidic or neutral isotonic saline. Blood flow was measured by laser Doppler velocimetry, and mucosal morphology was quantitatively evaluated by microscopy. RESULTS: Mucosal damage alone evoked a strong hyperemic response in both control and ablated rats. Ablated rats lost gastric protection despite this hyperemic response. Acid exposure after damage sustained the hyperemic response. Rapid epithelial restitution occurred faster (even over hemorrhagic lesions) in control rats. CONCLUSIONS: The hyperemic response to mucosal damage alone is not mediated by sensory neurons. Protection of the stomach by sensory afferent neurons occurs by mechanisms also unrelated to their elicitation of hyperemia. Restitution during acid challenge is enhanced by the sustained hyperemic response mediated through sensory afferent neurons.

Role of gastric blood flow in impaired defense and repair of aged rat stomachs.

To study impaired gastric mucosal tolerance against noxious agents in aged rats, possible factors underlying this observation were compared in anesthetized Fisher 344 young and aged rats. The gastric mucosa was damaged by in situ exposure to 80% ethanol for 30-45 s and by 1 M NaCl for 10 min followed by saline (pH = 1.0) for 60 min in chambered stomachs. The lesion area was significantly larger and epithelial restitution was significantly slower in aged than in young rats after both types of injury. Changes in gastric blood flow were monitored by laser-Doppler velocimetry. Young, but not aged, rats showed a marked increase in gastric blood flow in response to 1 M NaCl, acid challenge, and 640 microM capsaicin for 60 min. Young rats showed a higher density of calcitonin gene-related peptide (CGRP)-staining nerve fibers around submucosal blood vessels and higher mucosal release of prostaglandin E2 and leukotriene C4 than did aged rats. These data suggest that impaired mucosal defense and reduced restitution in aged rats is related to lack of hyperemic response caused by mucosal injury and H+ back-diffusion, which is probably due to decreased density of CGRP-staining nerve fibers and prostaglandin biosynthetic capacity in the mucosa.

Morbidity, ability to swallow, and survival, after oesophagectomy for cancer of the oesophagus and cardia.

OBJECTIVE: To study survival, morbidity, and ability to swallow, after oesophagectomy for cancer of the oesophagus and cardia. DESIGN: Prospective open study. SETTING: University hospital, Norway. SUBJECTS: 83 patients, 38 with squamous cell carcinoma and 45 with adenocarcinoma of the oesophagus and cardia. INTERVENTIONS: Transhiatal (n = 51) and transthoracic (n = 32) oesophagectomy. Oesophageal replacement was by either stomach (n = 80) or colon (n = 3). Cervical anastomosis was used in all but 2. MAIN OUTCOME MEASURES: Early and late morbidity and mortality, length of stay in intensive care unit and in hospital, and survival analysis. RESULTS: 30 Day and in hospital mortality were 0 and 4% for transhiatal, and 6% and 9% for transthoracic, oesophagectomy. Complications included recurrent nerve palsy (n = 7), anastomotic leaks (n = 5), and chylothorax (n = 4). 17 Patients (22%) needed dilatations for stenosis of the anastomosis, and 71 (85%) of the patients left hospital within four weeks of operation. Survival analysis showed a 5 year survival rate of 33% for patients with adenocarcinoma operated on for cure and a 2 year survival of 28% for patients with squamous cell carcinoma. CONCLUSIONS: Oesophagectomy for cure is worthwhile as some patients are cured and most of the remainder have prolonged relief of their dysphagia. Palliative resections should not be done in patients with distant metastases or invasion of adjacent organs by the tumour because of long stay in hospital, appreciable morbidity, and short life expectancy.

Burst abdomen and incisional hernia after major gastrointestinal operations--comparison of three closure techniques.

OBJECTIVE: To compare the incidence of burst abdomen and incisional hernia after three different techniques of closure of the abdominal wall after major gastrointestinal operations. DESIGN: Prospective, randomised, controlled trial. SETTING: University hospital, Norway. SUBJECTS: 599 adults who underwent major operations for gastrointestinal conditions between December 1990 and February 1992. INTERVENTIONS: Patients were randomised in three groups for abdominal wall closure by continuous mass polyglyconate (Maxon) double suture with loop, continuous mass polyglactin 910 (Vicryl), and interrupted polyglactin 910 (Vicryl) (layered for transverse and mass for midline incisions). MAIN OUTCOME MEASURES: Burst abdomen during the postoperative period, and incisional hernia after one year follow up. RESULTS: The incidence of wound dehiscence was 2% and of incisional hernia at one year 7%. There were no differences in the rate of dehiscence among the groups, but there were significantly more hernias in the polyglyconate group (19/164, 12%) compared with the two in which polyglactin 910 was used (16/327, 5%). Wound infections developed in 84/583 of our patients (14%) and the incidence was closely associated with emergency operations and contamination. Wound complications were not associated with the closure technique. CONCLUSIONS: Wound infection is the most important single factor in the development of burst abdomen and incisional hernia. The continuous closure technique is quicker, cheaper, and as safe as the interrupted technique.

Gastric mucosal repair and release of HCO3- after damage by 2 M NaCl in cat: role of systemic acid base status.

To study the influence of acid base balance on gastric mucosal repair, NH4Cl or NaHCO3 was given intravenously to anesthetized cats after mucosal damage induced by intraluminal 2 M NaCl. Saline at pH 5 or 1 was perfused via an oral tube through the stomach lumen and evacuated via a pyloric tube to a chamber with pH and PCO2 electrodes. Luminal bicarbonate (HCO3-) was markedly increased early after damage in both acidotic and alkalotic animals. In alkalotic animals mucosal blood flow increased about twofold in response to mucosal damage, whereas the early hyperemic response was either completely attenuated or blunted in acidotic animals. HCO3- release was correlated to availability of HCO3- by blood in alkalotic animals with luminal pH 5. Alkalotic animals showed improved repair compared with acidotic animals, and mucosal restitution was correlated to availability of HCO3- by blood. We conclude that luminal leakage of HCO3- or plasma after mucosal damage depends on availability by blood and consumption of HCO3- within the mucosa and that blood borne HCO3- has a major influence on gastric mucosal repair.

Role of bicarbonate in blood flow-mediated protection and repair of damaged gastric mucosa in the cat.

BACKGROUND/AIMS: The hyperemic response after superficial gastric mucosal damage is essential for repair of the mucosa. Only indirect evidence suggests that this is caused by supply of bicarbonate. Therefore, this study tested the effect of maintaining the availability of bicarbonate after prevention of the hyperemic response after damage by 2 mol/L NaCl. METHODS: Celiac artery flow was reduced, as monitored by Doppler ultrasonography, by gradual constriction of the vessel after mucosal damage. Saline (pH 1.0) was perfused through the stomach lumen and thereafter through a closed chamber with pH and PCO2 electrodes. RESULTS: Exposure to 2 mol/L NaCl produced a marked increase of mucosal blood flow as measured by microspheres (P < 0.025) and a high degree of mucosal restitution 90 minutes after damage as judged by microscopy, whereas prevention of the hyperemic response caused extensive erosions and much less restitution (P < 0.001). The latter effect was completely counteracted by intravenous bicarbonate. High blood concentration of bicarbonate increased luminal release of bicarbonate, whereas high mucosal blood flow did not. CONCLUSIONS: These data show that bicarbonate is an important factor in blood flow-mediated protection and repair of damaged gastric mucosa and suggest that concentration gradients are the major determinants for transport of bicarbonate across the damaged and restituted mucosa.

Substance P attenuates gastric mucosal hyperemia after stimulation of sensory neurons in the rat stomach.

BACKGROUND/AIMS: Sensory neurons in the stomach mucosa are closely apposed to mast cells and blood vessels. Mucosal hyperemia, after exposure to capsaicin, is mediated by calcitonin gene-related peptide (CGRP) from these neurons, which also contain substance P (SP). However, the role of this peptide in blood flow regulation remains unclear. Therefore, this study examines the effect of SP on capsaicin-induced mucosal hyperemia and mast cells. METHODS: Gastric mucosal blood flow was measured with laser Doppler flow velocimetry in chambered rat stomachs. SP, aprotinin (serine protease inhibitor), and ketotifen (mast cell stabilizer) were infused into the splenic artery of rats. Mast cells were counted by microscopy. RESULTS: Mucosal exposure to capsaicin (640 mumol/L) evoked a 70% increase in mucosal blood flow, which was abolished by SP, whereas aprotinin infused with SP and pretreatment with ketotifen before SP infusion restored the hyperemic response. Morphometry showed that ketotifen inhibited mast cell degranulation in SP-treated animals. Preservation of mast cells in SP-treated rats was linearly correlated to increased mucosal blood flow after exposure to capsaicin. CONCLUSIONS: These data suggest that SP participates in regulation of gastric mucosal blood flow by activation of mast cells most likely by releasing proteases from mast cells that cleave and inactivate CGRP.