Acute and chronic surgical vagotomy (SV) and gastric mucosal vascular permeability in ethanol treated rats.

The role of vagus nerve was studied in the development of gastric mucosal damage induced by ethanol (ETOH). The investigations were carried out on Sprague-Dawley rats. The gastric mucosal damage was produced by i.g. administration of 1 ml 96% ETOH. Acute surgical vagotomy (ASV) was carried out 30 min, chronic surgical vagotomy (CSV) 14 days before the ETOH application. The animals were sacrificed at 0, 1, 5, 15, 60 min after ETOH. Evans blue (EB) (1 mg/100 g) was given i.v. 15 min before autopsy. The number and severity of lesions the EB accumulation of the gastric juice and gastric mucosa were noted. It was found, that: 1. The vascular permeability increased after ETOH treatment at an early state (within 1-5 min) in association to the macroscopic appearance of erosions. 2. The number and extension of lesions, the EB concentrations in gastric juice and gastric mucosa were significantly higher both after ASV and CSV. 3. Surgical vagotomy alone did not increase the vascular permeability. 4. No significant ulcer formation was observed in vagotomized rats without ETOH treatment. It was concluded, that 1. Both ASV and CSV enhanced the development of gastric mucosal injury induced by ethanol. 2. Neither acute nor chronic surgical vagotomy exerted an effect of the development of mucosal injury and vascular permeability without the application of the noxious agent. 3. The further increase of enhanced vascular permeability by vagotomy probably has an etiologic role in the aggravating effect of ASV and CSV on the development of chemical-induced lesions.     

Effect of autonomic denervation on DNA synthesis during liver regeneration after partial hepatectomy

The regulatory role of autonomic nerves in liver regeneration after partial hepatectomy was studied in rats by bilateral subdiaphragmatic vagotomy or splanchnicectomy. 1. In control rats the wet weight of the regenerating liver was restored to approximately 80% of the preoperative weight 72 h after partial hepatectomy. Restoration of the liver weight was significantly impaired in vagotomy rats, but not in splanchnicectomy. Increases in the DNA and protein contents of the regenerating liver were also suppressed by vagotomy. 2. Hepatic DNA synthesis, measured as the incorporation of [methyl-3H]thymidine into DNA at various times after partial hepatectomy, was significantly less in vagotomized rats, and slightly more in splanchnicectomized rats than in control rats. The onset of DNA synthesis triggered by partial hepatectomy was also delayed by vagotomy. 3. The increases in activities of hepatic aspartate transcarbamoylase and thymidine kinase, the key enzymes in synthesis of pyrimidine nucleotides via the de novo and salvage pathways respectively, during liver regeneration, were significantly suppressed and retarded in vagotomized rats. Conversely, splanchnicectomy tended to stimulate these enzyme inductions after partial hepatectomy. 4. During starvation the plasma insulin level decreased after partial hapatectomy in control and vagotomized rats, as in sham-operated rats, but showed a transient increase 6 h after partial hepatectomy in splanchnicectomized rats. It is concluded that vagotomy inhibits and delays DNA synthesis and proliferation of liver cells after partial hepatectomy, whereas splanchnicectomy tends to stimulate these processes. The data also suggest that parasympathetic innervation of the liver may play an important regulatory role in liver regeneration.     

Effects of phospholipase A2 on the etiology of pulmonary edema hemodynamics of lesser circulation in intact and vagotomized animals

In experiments on white rats, guinea pigs and cats it was shown that intravenous infusion of phospholipase A2 (FLA2) caused the development of pulmonary edema (PE) in guinea pigs, but did not cause it in rats and cats. Bilateral vagotomy on the neck led to the appearance of the expressed edemogenous effect of FLA2 on the lungs. Pentobarbital anesthesia decreased the effect of vagotomy. This effect is not connected with the turn off of the efferent impulsation in vagus nerves as the infusion of atropine did not repeat the influence of vagotomy. Authors assume that the action of FLA2 is realized across the secretion of humoral factor in vagotomized animals and the increase of the permeability of the aero-hematic barrier.     

Vagal nerve and the gastric mucosal defense

An essential role for an intact vagal nerve has been proven in the development of gastric mucosal cyto- and general protection. On the other hand, chemically-induced (ethanol, HCl, indomethacin) gastric mucosal damage is enhanced after acute surgical vagotomy. The aims of this paper were to study the possible mechanisms of the vagal nerve in the development of gastric mucosal defense. The following questions were addressed: 1) effect of surgical vagotomy on the development of ethanol- (ETOH), HCl-, and indomethacin (IND)-induced gastric mucosal damage; 2) changes in the gastric mucosal defense by scavengers, prostacyclin and other compounds (small doses of atropine and cimetidine: 3) changes in the gastric mucosal vascular permeability due to chemicals; 4) effect of indomethacin in the ETOH and HCl models with and without surgical vagotomy; 5) changes in the gastric mucosal content of prostacyclin and PGE₂ in the ETOH and HCl models after surgical vagotomy; and 6) changes in the role of SH-groups in gastric mucosal defense after surgical vagotomy. It was found that: 1) the gastric mucosal damage produced by chemicals (ETOH, HCl, and indomethacin) was enhanced after surgical vagotomy; 2) the cyto- and general gastric protective effects of β-carotene, prostacyclin, and small doses of atropine and cimetidine disappeared after surgical vagotomy; 3) the vascular permeability due to chemicals (ETOH, HCl, indomethacin) significantly increased after surgical vagotomy in association with an increase in both number and severity of gastric mucosal lesions; 4) IND alone (in animals with an intact vagus) did not produce gastric mucosal lesions (in 1-h experiments), but it aggravated ETOH-induced gastric mucosal damage (both its number and severity); 5) the gastric mucosal levels of prostacyclin and PGE₂ decreased after surgical vagotomy; 6) IND application (after surgical vagotomy) decreased further the tissue levels of prostacyclin and PGE₂ in association with an increase of gastric mucosal damage; and 7) the gastric mucosal protective effects of SH-groups were abolished by surgical vagotomy.     

Evaluation of early gastric mucosal permeability induced by central thyrotropin-releasing hormone administration

Accumulating evidence suggests that central thyrotropin-releasing hormone (TRH) administration induces gastric erosion 4 h after administration through the vagal nerves. However, early changes in the gastric mucosa during these 4 h have not been described. To assess early changes in the gastric mucosa after intracisternal injection of a stable TRH analog, pGlu-His-(3,3'-dimethyl)-ProNH2 (RX-77368), we measured the blood-to-lumen 51Cr-labeled EDTA clearance and examined the effects of vagotomy, atropine, omeprazole, and hydrochloric acid (HCl) on RX-77368-induced mucosal permeability. A cytoprotective dose of RX-77368 (1.5 ng) did not increase mucosal permeability. However, higher doses significantly increased mucosal permeability. Permeability peaked within 20 min and gradually returned to control levels in response to a 15-ng dose (submaximal dose). Increased mucosal permeability was not recovered after a 150-ng dose (ulcerogenic dose). This increase in permeability was inhibited by vagotomy or atropine. Intragastric perfusion with HCl did not change the RX-77368 (15 ng)-induced increase in permeability, but completely inhibited the recovery of permeability after the peak. Pretreatment with omeprazole did not change the RX-77368 (15 ng)-induced increase in permeability, but quickened the recovery of permeability after the peak. These data indicate that the RX-77368-induced increase in permeability is mediated via the vagal-cholinergic pathway and is not a secondary change in RX-77368-induced acid secretion. Inhibited recovery of permeability on exposure to an ulcerogenic RX-77368 dose or on exposure to HCl plus a submaximal dose of RX-77368 may be crucial for the induction of gastric mucosal lesions by central RX-77368 administration.     

Changes in rat liver mitochondria under conditions of bilateral subdiaphramatic vagotomy]

A study was made of the changes in the mitochondria of the rat liver under conditions of bilateral subphrenic vagotomy. Two stages in the dynamics of the response of the mitochondrial apparatus to denervation were distingished. During the first stage (0.5-3 days after vagotomy) there occurred reversible functional disturbances of the mitochondria caused by the postoperative stress. The second stage (7 to 60 days after the denervation) was charaterized by more marked structural-functional changes having a number od common features with those seen in hypoxia and being result of vagotomy proper.     

Difference between the effect of acute and chronic surgical vagotomy on the cytoprotective action of atropine against indomethacin-induced mucosal lesions on the gastrointestinal tract in rats

The cytoprotective effect of a small dose of atropine was proved against the indomethacin (IND)-caused gastrointestinal (GI) mucosal damage. This protective effect of atropine disappeared in the acute phase of surgical vagotomy (ASV) on the vagally-innervated parts of GI tract. The aims of our observations were: 1) to examine the effect of chronic surgical vagotomy (CSV) on the cytoprotective action of atropine in the GI tract; and 2) to compare the effects of ASV and CSV on the GI cytoprotection caused by atropine against IND-induced mucosal damage and vascular permeability in rats. The IND was given s.c. 24 h prior to the killing of the animals in a dose of 20 mg x kg(-1). Bilateral surgical vagotomy or sham operation were carried out 24 h (ASV) or 14 d (CSV) before IND-application. Atropine was given i.p. every 5 h after IND-treatment in a dose of 0.1 mg x kg(-1). The number of macroscopical mucosal ulcerations was noted and its severity was calculated by semiquantitative scale in the stomach, small intestine and three equal parts of colon. Vascular permeability was measured by Evans-blue leakage into the mucosal tissue. It has been found that: 1) Tte small dose of atropine significantly decreased the IND-induced mucosal damage and vascular permeability on the stomach, small intestine and the vascular permeability on the proximal colon; 2) the small dose of atropine did not cause any changes in the appearance of IND-induced mucosal lesions and in Evans blue concentration in the mucosa after ASV, but it significantly decreased the IND-caused mucosal damage and Evans blue concentration in the mucosa of stomach, small intestine and proximal colon after CSV; 3) the IND-induced mucosal damage and vascular permeability treated with atropine (given in cytoprotective dose) were significantly smaller after CSV than that after ASV on the stomach, small intestine and proximal colon. It has been concluded that the intact vagal nerve has an essential role in the appearance of cytoprotective mechanisms of atropine in GI tract.     

Vagotomy enhances experimental metastases of 4THMpc breast cancer cells and alters substance P level

We have previously demonstrated that inactivation of capsaicin-sensitive sensory neurons enhances lung and heart metastases of breast carcinoma. Because a significant part of sensory innervation of lung tissue is supplied by the vagus nerve, we here examined the effects of unilateral mid-cervical vagotomy in the metastases of 4THMpc breast carcinoma and tissue Substance P (SP) levels. Balb-c mice were injected orthotopically with 4THMpc cells 1 week after vagotomy. Animals were sacrificed 27-30 days after injection of 4THMpc cells and the extent of metastases was determined. Unilateral vagotomy, right or left significantly increased the lung, liver and kidney metastases without altering the growth rate of the primary tumor. Heart metastases were increased only following left vagotomy. The changes in SP levels were somewhat surprising such that vagotomy actually increased while sham-operation decreased SP levels in lung. The effect of sham-operation was reversed by unilateral vagotomy demonstrating that vagal activity decreases total SP levels in the lung. Increased SP levels might be due to decreased degradation of the peptide. Presence of the tumor markedly increased SP level in the lung, which was more prominent in vagotomized animals. These results provide evidence that vagal activity may protect against metastatic disease.     

The role of the parasympathetic nervous system in regulating the oxygen tension and regional blood flow in the digestive organs of rats

The input of parasympathetic region of vegetative nervous system in regulation of regional blood transfer and maintaining of oxygen balance in organs of rat digestive system has been estimated by measuring oxygen tension (pO2) and the rate of regional blood transfer (RBTR) in liver, gut, and small intestine after 1, 7, 14, 30, and 60 days after vagotomy. Vagotomy was shown to lead to the decrease of pO2 in liver (1, 14, 30 days), gut (1 day), and small intestine (7 and 30 days). At initial postoperation period (1 day), the decrease in pO2 is accompanied by the increase in RBTR (in gut and small intestine), and at late period, by the decrease of RBTR in liver. The correlation between the decrease in pO2 and the decrease in RBTR allows to conclude that the hypoxia developing in liver after vagotomy is of a circulatory nature.     

Morphologic and histochemical indices of hepatic function following bilateral subdiaphragmatic vagotomy

A complex morpho-functional investigation of the rat liver was performed after bilateral subdiaphragmal vagotomy by means of light, electron microscopy methods and a quantitative histochemical method. Some ultrastructural disorders in hepatocytes and in stellate reticuloendotheliocytes were revealed, with their maximal manifestation 7 days after vagotomy. At later stages (45 and 90 days), compensatory-restorative processes develop resulting in considerable (but not complete) normalization of the organ's structure. Quantitative histochemical investigations have demonstrated that even at the highest degree of the resulted disorders the liver preserves its ability to synthesize and accumulate glycogen, but the intensity of the process is considerably lowered. Functional changes are reversible in their character and correlate to the degree of structural disorders.     

Use of dibunol in pharmacological correction of post-vagotomy hypoxia of digestive organs in rats

1, 7, 14, 30 and 60 days after bilateral sub-diaphragmatic truncal vagotomy tension of oxygen (pO2) in liver, stomach and small intestine (jejunum) was determined. It was demonstrated that vagotomy leads to a decrease of pO2 in all investigated organs 1 day after the operation (such changes were observed in sham-operated rats) and 30 days, in jejunum--after 7 days, in liver--after 14 days, in stomach--after 60 days. Dibunol introduction in vagotomized rats during 29 days (starting from the second day after operation) results in pO2 normalization in all investigated organs.     

Correlation between the cytoprotective effect of beta-carotene and its gastric mucosal level in indomethacin (IND) treated rats with or without acute surgical vagotomy.

As to earlier observations that beta-carotene prevents the development of gastric mucosal injury produced by different noxious agent, however, its cytoprotective effect can be abolished by acute surgical vagotomy. The aim of this study was to evaluate the possible correlation between the gastric mucosal cytoprotective effect of beta-carotene and its gastric mucosal level in rats treated with IND. The gastric mucosal damage was produced by the administration of IND (20 mg/kg s.c.). The instillation of beta-carotene and acute surgical vagotomy (ASV) or SHAM operation were carried out 30 min before IND treatment. The rats were sacrificed 4 h after IND application, and the number and severity of gastric mucosal erosions were noted. The blood rats was collected quantitatively, the liver and the gastric mucosa were removed, and the beta-carotene and vitamin A level of the gastric mucosa, serum and liver were measured with HPLC. It was found that: 1. Beta-carotene induced gastric cytoprotection in SHAM-operated rats treated with IND but its effect disappeared after ASV. 2. Although the beta-carotene level of the gastric mucosa increased its concentration was not elevated in the serum of intact and vagotomized animals either. 3. Vitamin A Formation was not detected in the liver of animals with or without ASV. It was concluded that the lack of intake of beta-carotene into the gastric mucosa can not play etiologic role in the failure of gastric cytoprotection of rats with acute bilateral surgical vagotomy.     

Characteristics of liver regeneration after vagotomy

Peculiarities of a reparative process in the hepatic parenchyma have been studied after toxic effect of CCl4, at vagotomy in 1, 2 and 4 weeks after the operation. Appearance of a more massive lesion and decreasing regeneration of the vagotomized liver have been revealed. The proliferative activity of hepatocytes, normal and after vagotomy has a principally similar character and is described as a curve with two picks, having its maximum on the 2nd and the 5th-6th days after xenobiotic administration. The intensity of the hepatocyte proliferative activity in the denervated liver essentially surpasses that in the control and decreases, as the area of the parenchymal lesion decreases in the latest time after the operation.     

Effect of denervation of the liver on the system of microsomal oxidation in adult and old rats

The role of adrenergic and cholinergic neural regulation in the functional activity of the liver microsomal oxidation enzymes has been studied. The experiments on adult and old rats using surgical denervation of the liver (vagotomy and sympathectomy++) have revealed changes in the monooxygenase activity (aminopyrine demethylase and aniline hydroxylase), in isoform composition and inductive synthesis of cytochrome P-450. The neural control over detoxication function of the liver is found to weaken in old age.     

Effects of truncal,selective, and highly selective vagotomy on glucose tolerance and insulin secretion in patients with duodenal ulcer. Part II-Comparison of response to oral and intravenous glucose.

Paired oral and intravenous glucose tolerance tests were carried out in patients who had undergone truncal vagotomy and pyloroplasty, selective vagotomy and pyloroplasty, or highly selective vagotomy at least six months earlier. Intravenous glucose tolerance was similar in all three groups. Oral glucose elicited significantly higher concentrations of plasma insulin in patients who had undergone selective and highly selective vagotomy than in those treated by truncal vagotomy. When the same amount of glucose was given intravenously, however, plasma insulin concentrations were similar in all three groups of patients. The insulin secreted in response to intravenous glucose expressed as a percentage of that secreted in response to oral glucose was 112% for truncal vagotomy, 51% for selective vagotomy, and 52% for highly selective vagotomy. Truncal vagotomy thus led to a diminished insulin response to oral glucose, which was probably due to impaired release of small-bowel hormones.     

Action of hepatic chalones on the proliferation of hepatocytes from intact and denervated livers

The paper is concerned with the action of chalones, tissue-specific inhibitors of cell proliferation, on DNA synthesis and mitotic activity of hepatocytes in the intact and denervated liver during regeneration. Experiments were made on Wistar rats. Liver denervation was performed by bilateral subdiaphragmal vagotomy. In control and vagotomized animals, two thirds of the liver was resected. The data obtained indicate that chalones noticeably reduce the number of DNA-synthesizing cells and mitoses in the regenerating liver of intact animals. During regeneration of the denervated liver, chalones do not produce any inhibitory action on the intensity of proliferation. Analysis of the data obtained allows a conclusion that preservation of adequate innervation of the organ is needed for realization of the action of hepatic chalones.     

Incidence of Dumping after Truncal and Selective Vagotomy with Pyloroplasty and Highly Selective Vagotomy without Drainage Procedure

The incidence of dumping after truncal or selective vagotomy with pyloroplasty and highly selective vagotomy without a drainage procedure was assessed both clinically and experimentally. At a gastric follow-up clinic dumping was found to be significantly less frequent in patients who had undergone highly selective vagotomy without a drainage procedure than in patients who had undergone truncal or selective vagotomy with pyloroplasty (P < 0·05 or < 0·001, respectively). Hypertonic glucose given by mouth provoked the onset of dumping in 20% of patients with duodenal ulcer before operation, in 73% after truncal vagotomy and pyloroplasty, in 80% after selective vagotomy and pyloroplasty, and in 47% after highly selective vagotomy. The test meal also produced significantly greater decreases in blood pressure and increases in pulse rate in patients who had undergone vagotomy with pyloroplasty than in patients who had undergone highly selective vagotomy.     

Five- to Eight-year Results of Truncal Vagotomy and Pyloroplasty for Duodenal Ulcer

From January 1963 to December 1965 inclusive 192 men with duodenal ulcer were treated by elective truncal vagotomy and pyloroplasty with one death. Ten subsequent deaths were due to causes unrelated to the ulcer or operation, and 17 patients became untraceable. The remaining 164 patients have been followed up for five to eight years. The late results have been compared with those obtained in a previous study of patients five to eight years after truncal vagotomy and gastroenterostomy, truncal vagotomy and antrectomy, and subtotal gastrectomy respectively for duodenal ulcer.Of the various postgastric operation syndromes early dumping, late dumping, bilious vomiting, and diarrhoea were all less frequent, but not significantly so, after vagotomy and pyloroplasty than after vagotomy and gastroenterostomy.Recurrent ulceration was commoner after vagotomy and pyloroplasty than after all the other operations, the incidence of proved and suspected recurrent ulcers being respectively 6·7 and 7·3% after vagotomy and pyloroplasty, but only 2·5 and 5·9% after vagotomy and gastroenterostomy, 0 and 5·2% after vagotomy and antrectomy, and 0·9 and 3·7% after subtotal gastrectomy. The differences between vagotomy and pyloroplasty and vagotomy and antrectomy or subtotal gastrectomy are statistically significant, but those between vagotomy and pyloroplasty and vagotomy and gastroenterostomy are not.Overall assessment (Visick grading) of the outcome gave poorer results after vagotomy and pyloroplasty than after any other operation, with 14% of category IV cases after vagotomy and pyloroplasty, 11% after vagotomy and gastroenterostomy, 8% after vagotomy and antrectomy, and 6% after subtotal gastrectomy—differences that are significant between vagotomy and pyloroplasty and vagotomy and antrectomy or subtotal gastrectomy but not between vagotomy and pyloroplasty and vagotomy and gastroenterostomy.In the light of these findings it is suggested that truncal vagotomy and pyloroplasty has not lived up to expectations and its place as the currently most popular procedure in the elective surgical treatment of duodenal ulcer should be reconsidered.     

Effect of tidal volume and anesthetic agent on airway responsiveness to histamine

Dose-response relationships for bronchoconstriction in response to aerosal histamine were assessed before and after vagotomy in 11 dogs anesthetized with barbiturates and in 9 dogs anesthetized with alpha-chloralose-urethan. The dose-response relationships following vagotomy were assessed during spontaneous ventilation and during muscular paralysis and mechanical ventilation with tidal volume (VT) similar to each animal's VT prior to vagotomy. After vagotomy the spontaneous VT of both groups increased but the VT of the alpha-chloralose-urethan group was significantly less than that of the barbiturate group. The histamine responsiveness of the animals anesthetized with barbiturates was significantly greater during mechanical ventilation when VT was reduced to prevagotomy levels compared with during spontaneous ventilation. In contrast, the histamine responsiveness of the alpha-chloralose-urethan group was not significantly changed by reducing VT to prevagotomy levels. In six other dogs anesthetized with pentobarbital sodium and studied after vagotomy, responsiveness to histamine aerosol during controlled ventilation with breaths of prevagotomy VT was greater than responsiveness during mechanical ventilation with large volume breaths given immediately afterward. Thus the magnitude of VT of dogs after vagotomy may influence airway responsiveness, and the influence of anesthetic agents on airway responsiveness after vagotomy may in part be due to their effects on VT. Furthermore, bronchodilation accompanying large volume ventilation persists after vagotomy, suggesting that it is not exclusively mediated by changes in parasympathetic activity.     

Effects of truncal,selective, and highly selective vagotomy on glucose tolerance and insulin secretion in patients with duodenal ulcer. Part I-Effect of vagotomy on response to oral glucose.

An oral glucose tolerance test was performed in patients who had undergone truncal vagotomy and pyloroplasty, bilateral selective vagotomy and pyloroplasty, or highly selective vagotomy without a drainage procedure at least six months earlier. The results were compared with those from patients with chronic duodenal ulcer before operation. In all three groups of patients after vagotomy more rapid rates of rise of blood glucose and higher peak concentrations were observed than in patients who were tested before operation. These differences were statistically significant only in patients who had undergone truncal or selective vagotomy with pyloroplasty and were probably due to more rapid rates of gastric emptying after these operations. Plasma insulin concentrations were lower after truncal vagotomy than after selective or highly selective vagotomy, the difference between truncal vagotomy and highly selective vagotomy being statistically significant. Truncal vagotomy resulted in a diminished insulin response to oral glucose, which could have been due to vagal denervation of the pancreas or, more probably, impaired release of small-bowel hormones which normally augment the pancreatic insulin response.