The effects of general anaesthesia on antroduodenal motility, gastric pH and gastric emptying in man

This survey was based on five recently published papers. The aims of the studies were to to investigate the effect of general anaesthesia on antroduodenal motility, gastric pH and gastric emptying. Antroduodenal motility was measured by manometry, gastric pH by a stomach microelectrode and gastric emptying rate using paracetamol absorption as an index. Two studies deal with antroduodenal motility during basal conditions and after administration of paracetamol and diazepam in 11 healthy volunteers. Three studies deal with the effects of 4 different methods of general anaesthesia on antroduodenal motility, gastric pH and gastric emptying rate in 43 patients undergoing orthopedic or plastic surgery not involving the abdomen having four different methods of general anaesthesia. In the healthy volunteers a close connection between antral activity and gastric emptying rate was found. Paracetamol had no effects on gastric pH. The changes in motility (a shortening of phase III and a decline in the incidence of antral phase III activity) were minor and ascribed to diurnal variations and by a possible stimulation of antral activity by the positioning of the manometric tube. It was found that no paracetamol was absorbed in the quiescent phase I, irrespective of its duration, and that the absorption rate of paracetamol correlated with the duration of phase II and the occurrence of antral activity during phases II and III. The effects of premedication with diazepam on antroduodenal motility, gastric pH and gastric emptying rate was investigated in the same healthy volunteers prior to the patient studies. Also in this study a correlation between antral activity and gastric emptying rate was found. Furthermore, it was observed that some volunteers had fast gastric emptying rate, indicated by fast absorption of paracetamol, the first study day and slow the second. It seemed that any intra- or interindividual variation in gastric emptying rate arises from individual variations in antroduodenal motility. Diazepam tended to increase gastric emptying rate by enhancing the amplitudes of antral contractions and the motility index during phase II and pH of the gastric juice increased. Gastroduodenal motility was found to be normal in patients awaiting elective orthopedic or plastic surgery when premedicated with diazepam. pH of the gastric contents was not different from the findings in volunteers after administration of diazepam. All methods of general anaesthesia reduced the duration of the interdigestive motility complex, mainly by a reduction of phase II. General anaesthesia with halothane and enflurane depressed antral motility.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of ranitidine and cimetidine on experimentally induced ventricular arrhythmias in anaesthetized rats

The effects of two histamine H₂-receptor antagonists, ramitidine and cimetidine, on ventricular arrhythmias induced by acute coronary artery ligation and by aconitine infusion were studied in pentobarbitone-anaesthetized rats. The changes in arterial blood pressure and heart rate were also observed. It was found that both drugs significantly reduced the incidence, and prolonged the time of onset, of ventricular tachycardia and ventricular fibrillation following acute coronary artery ligation; however, they did not significantly alter the incidence or time of onset of ventricular dysrhythmias caused by aconitine infusion. These findings further support the hypothesis that histamine release may contribute to the genesis of early ventricular arrhythmias resulting from acute myocardial ischaemia. Since the decreased blood pressure induced by coronary artery ligation was not significantly prevented by pretreatment with either histamine H₂-receptor blocker, this suggests that histamine may not be responsible for the blood pressure changes during acute myocardial ischaemia.     

Endocrine effects of the H2-receptor antagonists cimetidine and ranitidine

This paper reviews investigations on the endocrine effects of two H2-receptor antagonists, cimetidine and ranitidine. Cimetidine has hyperprolactinaemic properties and interferes with the peripheral activity of the sexual hormone (DHT) and probably with the pituitary LH secretion. A possible effect on TSH and thyroid hormone secretion or peripheral metabolism is suggested. Ranitidine seems to have no central or peripheral effects (after both acute and chronic administration) on sexual hormones. High doses (300 mg i.v. bolus) of the drug induce a significant increase in prolactin basal levels, whereas no effects follow oral administration. The effects on PRL are sex-related and less marked than those obtained with cimetidine. The chronic administration of this drug does not affect basal or TRH-stimulated PRL levels. No effects were apparent on TSH serum levels after either oral or i.v. acute administration, whereas lower basal and TRH-stimulated T4 values were registered after chronic treatment. On the basis of these results, a possible interference of ranitidine on iodothyronine metabolism can be suggested.     

Comparison of inhibitory effects of atropine, cimetidine, and atropine plus cimetidine on the indomethacin-provoked gastric mucosal erosions in rats

20 mg/kg-1 indomethacin suspended in 1% carboxymethyl-cellulose solution was given subcutaneously into rats to provoke gastric mucosal erosions during 5 h. Dose-dependent inhibitions of indomethacin erosions were observed following different doses of atropine (0.025; 0.2; 1.0 mg/kg-1) and cimetidine (2.5; 10; 50 mg/kg-1) administered intraperitoneally (25%; 38%; 81% and 0%; 42%; 89% respectively). More pronounced inhibitory effects have been obtained with the combinations of both drugs (51%; 68%; 92%). In particular there was a remarkable potentiated synergism in the lowest doses of atropine and cimetidine (51%, against 0% and 25%). These results provide further evidence of synergism of histamine H2-receptor blockers and anticholinergics, which combinations would be useful, for example, in peptic ulcer therapy.     

Cardiovascular effects of ranitidine and cimetidine during acute myocardial ischaemia in anaesthetized dogs

The effects of ranitidine and cimetidine on ventricular fibrillation threshold and haemodynamics were studied in pentobarbitone-anaesthetized dogs subjected to acute coronary artery ligation. These drugs did not significantly change the ventricular fibrillation threshold nor haemodynamics before coronary artery ligation, except for remarkable haemodynamic depression by ranitidine 1 mg/kg. Ligation of the left anterior descending coronary artery reduced the ventricular fibrillation threshold, decreased systemic and left ventricular pressure and myocardial contractility, and slightly increased heart rate. Pretreatment with ranitidine 0.25 or 1 mg/kg, or with, cimetidine 2 mg/kg, significantly abolished the reductions in ventricular fibrillation threshold, but did not noticeably alter the haemodynamic changes. These findings further support the hypothesis that histamine release may contribute to the increased ventricular vulnerability resulting from acute myocardial ischaemia. However, the role of histamine in the haemodynamic responses to coronary artery ligation remains obscure.     

Comparison of the effects of cimetidine and ranitidine in histamine provocation tests in atopic asthma

The effects of cimetidine and ranitidine on the bronchial reactivity in the group of 10 patients with atopic bronchial asthma are presented. The patients received 800 mg of cimetidine daily for 6 days and, after a three-day interval, 300 mg of ranitidine daily for a further 6 days. Bronchial reactivity to histamine was determined before the administration of each drug and on the third and sixth days of each course of treatment. A comparison of the effect of cimetidine and ranitidine on the bronchial reactivity of the same patients revealed that after 3 days' exposure to each of the two drugs, cimetidine enhanced bronchial reactivity to a statistically (p<0.05) greater extent than ranitidine. Bronchial reactivity was found to increase significantly after 6 days of treatment with each of the drugs but no statistically significant differences were noted on comparing the effect of these drugs. The results seem to indicate that H₂ receptor antagonists may cause bronchoconstriction in some patients with bronchial asthma. The blocking effect depends on the type of the drug used and is connected with the chemical structure of the compounds.This work was supported by the Polish Academy of Science Grant No. 06.03.     

Therapeutic effects of cimetidine on acetaminophen-induced hepatotoxicity in rats

Acetaminophen is a widely used analgesic and antipyretic drug. An overdose can cause life-threatening hepatotoxicity in humans and experimental animals. In this study, 80 female Sprague–Dawley rats randomized into eight groups (three control and five test groups) were used. Three milligrams per kilogram acetaminophen was administered orally to induce liver necrosis. Cimetidine (12.5 mg/kg) was administered intraperitoneally at 0, 1, 2, 4, and 8 h after acetaminophen administration. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and extent of pathologic changes in liver were evaluated in all groups (1–8), and were found to be increased in group 2 (acetaminophen control), but not in groups 1 and 3 (control groups), and were decreased in some treatment groups. The decrease observed in groups 7 and 8 was more than that in group 6. However, in these groups, more animals died due to toxicity before blood sampling. It was concluded that injection of cimetidine 2 h after acetaminophen administration (group 6) can markedly decrease the serum levels of ALT, AST, and the extent of pathologic lesions in the liver with minimal toxicity and death.     

Comparison of antiproliferative effects of 1-histamine-2 receptor antagonists,cimetidine, ranitidine,and famotidine,in gastric cancer cells

In the immune system, histamine is known to suppress cytotoxic T-lymphocytes and mitogen induced lymphocyte thymidine uptake, down-regulate some cytokines, and activate suppressor T-lymphocytes, and in the gastrointestinal system, histamine was reported to have trophic effects on gastrointestinal epithelial cells. Enhanced rates of cell proliferation by histamine are implicated in the pathogenesis of carcinogenesis. This study was designed since there is a lack of comparative data about the cell proliferations of histamine-2 receptor antagonist (H2-RA), cimetidine, ranitidine, and famotidine, in gastric cancer. KATO-III and AGS cell lines were used in this experiment. The concentrations of the histamine and cimetidine were 10⁻⁵, 10⁻⁸M, respectively and those of ranitidine and famotidine were 10⁻⁶-10⁻⁹M, respectively. Cell proliferation after drug treatment was evaluated by direct cell counting, [³H]thymidine incorporation, and MTT assay. Activities of ornithine decarboxylase (ODC), a rate limiting enzyme in polyamine synthesis, were measured after each drug treatment. Protein kinase A, a cAMP-dependent protein kinase system, was assayed using [α-³²p]ATP. Histamine showed statistically significant cell proliferating effects in a dose-dependent manner (P < 0.01), the maximal effect in 10⁻⁵M concentration. ODC activities were increased in accordance with the increment of cell numbers after histamine treatment. Cimetidine reversed the histamine-stimulated cell proliferation significantly, the maximal effect in 10⁻⁵M concentration (P < 0.01). Although ranitidine showed the tendency to attenuate the cell proliferation dose-dependently, but without statistical significance, famotidine did not show such an effect at all. cAMP-dependent protein kinase activities were significantly increased following 10⁻⁵M histamine treatment, also reversed significantly by cimetidine co-administration (P < 0.01). Beneficial clinical outcomes could be anticipated from cimetidine treatment in patients with gastric cancer by anti-proliferating effects against gastric cancer cells. These effects of H2-RA are likely to be mediated by specific interactions at the H2-receptor.     

Effect of atropine and cimetidine combinations on pentagastrin stimulated maximal gastric acid secretion in man

Recently it has been reported that anticholinergics were able to increase the inhibitory effect on gastric secretion of specific histamine H2-receptor antagonists. The aim of the present study was to determine the degree of increased inhibition of gastric acid secretion and also to introduce an exact method for measuring the gastric acid output. Maximal gastric acid secretion provoked by continuous pentagastrin infusion 3.4-4.0 micrograms X kg-1 h-1) was dose-dependently inhibited by intravenous (i.v.) atropine (0.002; 0.003; 0.004 mg X kg-1) and cimetidine (1.0; 1.5; 2.0 mg X kg-1). A potentiated synergism was observed on the simultaneous administration of atropine and cimetidine, suggesting the good effect of a low dose combination of atropine and cimetidine in the therapy of peptic ulcer.     

The effects of cimetidine,ranitidine and famotidine on rat hepatic microsomal cytochrome P-450 activities

It has been questioned whether the interaction of H₂-antagonists with cytochrome P-450 that is observedin vitro is also relevant for thein vivo situation. Until now the possibility that cytochrome P-450 may function with different modes of action has been neglected in this respect. We studied the effect of cimetidine, ranitidine and famotidine on the monoxygenase, the oxidase and the peroxidase action of cytochrome P-450. Biotransformation catalyzed by the monoxygenase and oxidase action of cytochrome P-450 was affected by cimetidine (probably via its ligand interaction with cytochrome P-450), whereas metabolism by the peroxidase mode of action of cytochrome P-450 was hardly influenced. Ranitidine and famotidine (both pharmacodynamically more potent than cimetidine) only slightly affected cytochrome P-450 activities.     

Hedonics of taste influence the gastric emptying in rats

It is known that taste sensation plays important roles in various functions including appetite, nutriental choices, food intake and digestion. To study the modulation of digestive functions by taste stimulation, we measured the gastric emptying of experimental foods with appetitive or aversive tastes in Wistar male rats. Rats were randomly divided into 3 groups: each group was trained to eat a mash mixture (8 g) made up with powdered food (4 g) and a solution (4 g) for 30 min per day. The solution was either distilled water, saccharin solution as a palatable taste, or quinine solution as an aversive taste. On the test day, the contents of the stomach of each rat were measured before and 30, 150, or 300 min after the start of eating the mash. The results showed that the food output from the stomach was increased by the palatable mash and was decreased by the aversive mash in comparison with non-adulterated mash 150 min after eating. There were no significant differences in gastric emptying among the 3 groups after deafferentation of the two peripheral taste nerve branches, the chorda tympani and glossopharyngeal nerves, or after intragastric infusions of each mash. After the establishment of conditioned taste aversions to saccharin, saccharin mash became ineffective in increasing gastric emptying. These results show that hedonically positive tastes increase, but hedonically negative tastes decrease gastric function in terms of gastric emptying.     

Effects of cholecystokinin-octapeptide (CCK-8) on food intake and gastric emptying in man

Food intake and gastric emptying were measured simultaneously after cholecystokinin-octapeptide (CCK-8) and saline infusions in order to test the hypothesis that reduction in gastric emptying mediates the effect of CCK-8 on food intake. Each of twelve nonobese healthy men received intravenous infusions of CCK-8 and saline on separate nonconsecutive days after they had consumed 500 g of tomato soup tagged with technetium-99-DTPA. Intake of a test meal was measured 20 min after consumption of the soup while gastric emptying was simultaneously monitored by gamma emission scintigraphy of the soup. Food intake and gastric emptying of the soup were both significantly reduced by CCK-8 infusions in comparison to saline. There was a significant correlation between the amount of the test meal eaten and the amount of soup emptied during the period the test meal was being eaten, but not before the meal, only on days when CCK-8 was infused. Differences in intakes between days when saline was infused and days when CCK-8 was infused did not correlate with differences in gastric emptying of soup. These results suggest that CCK may amplify signals of satiety in proportion to the fullness of the stomach. Gastric emptying per se may not mediate the effects of CCK-8 on food intake.     

Inhibition of gastric acid secretion in the dog by the histamine H2-receptor antagonists ranitidine and cimetidine

The H₂-receptor antagonists ranitidine and cimetidine inhibit gastric acid secretion elicited by a test meal in the dog. Ranitidine is approximately 10 times more potent than cimetidine in this respect.     

Regulation of NaCl solution intake and gastric emptying in adrenalectomized rats

Adrenalectomized (adrex) rats adaptively increase NaCl intake to compensate for the uncontrolled loss of Na(+) in urine due to the absence of aldosterone. After a period of NaCl deprivation, they ingest saline avidly but stop drinking before hyponatremia is repaired. The present experiments determined whether pre-systemic signals inhibit further NaCl intake, and whether gastric emptying of Na(+) is modulated according to the concentration of ingested NaCl solution. After overnight deprivation, adrex rats consumed 0.05 M and 0.15 M NaCl at a maximally fast rate ( approximately 1.7 ml/min) and emptied ingested fluid from the stomach at a slower but maximally fast rate ( approximately 1.1 ml/min). When 0.30 M NaCl was consumed instead, fluid intake still was maximally fast but gastric emptying slowed in proportion to concentration so that the emptying of Na(+) was comparable to that observed when 0.15 M NaCl was ingested ( approximately 0.13 meq/min). When 0.50 M NaCl was consumed, intake slowed proportionately so that Na(+) consumption was comparable to that observed when 0.30 M NaCl was ingested ( approximately 0.5 meq/min). NaCl intake appeared to be inhibited both by the concentration of saline emptied from the stomach and by the volume of ingested fluid in the stomach and small intestine. Gastric emptying also slowed proportionately when 0.50 M NaCl was consumed, as if the rats were regulating the delivery of Na(+) to the small intestine. These results suggest that adrex rats can detect the volume and concentration of ingested NaCl solution presystematically and integrate these two variables, and thereby modulate the rates of Na(+) intake and gastric emptying.     

Serotonin involvement in the electroacupuncture- and moxibustion-induced gastric emptying in rats

OBJECTIVE: Electroacupuncture (EA) as well as moxibustion stimulation has been reported to produce an excitatory effect on the gastrointestinal motility of the rat. Serotonergic neurons of the mioenteric and submucous plexus are major participants in the gastrointestinal physiology. Here, we compared the outcomes of the stimulation of a specific set of acupoints with either acupuncture or moxibustion on the gastrointestinal motility and the role of serotonin (5-HT) in this effect. METHODS: To analyze the role of 5-HT on the gastrointestinal motility of the rat, we studied the flow of 25 glass beads administered to the stomach, after treatment of the animals with a serotonin inhibitor (para-chlorophenylalanine [pCPA]). Acupuncture stimulation was performed on acupoints St-36 (Zusanli) and Sp-6 (Sanyinjiao), with electrical stimulation, or on acupoints Ren-10 (Xiawan), Ren-12 (Zhongwan) and St-25 (Tianshu), with moxibustion. Animals subjected to sham stimulation were used as controls in addition to naive, unstimulated animals. RESULTS: Stimulation of the hind limb (St-36 and Sp-6) and abdominal (Ren-10, Ren-12, St-25) acupoints resulted in effective gastric emptying, as compared with sham-stimulated animals. Pretreatment of animals with pCPA abolished either the response provided by acupuncture stimulation in animal groups subjected to hind limb acupoints or the response provided by moxibustion stimulation in abdominal acupoints. CONCLUSION: Our data suggest that moxibustion in the abdominal points and EA in the hind limb require an intact serotonergic pathway. In addition, we suggest that this involvement of serotonin is a general feature of the mediated effects of acupuncture on gastric emptying of the rat.     

Effect of pentacaine and ranitidine on gastric mucus changes induced by cold-restraint stress in rats

The potential involvement of increased mucus secretion in the antiulcer activity of a cytoprotective agent, pentacaine, and of the H₂-antagonist ranitidine was studied in stressed rats. Cold-restraint stress decreased the gastric mucus content and induced haemorrhagic erosions in the stomach. Pretreatment with pentacaine and ranitidine dose-dependently diminished the extent of stress-induced gastric damage. Pentacaine prevented the depletion of mucus after stress, while ranitidine failed to affect it. In nonstressed rats only pentacaine was able to enhance mucus secretion. The stimulating effect of pentacaine on gastric mucus secretion may account for some of its antiulcer properties.