Effects of dipyrone on the digestive tract.

Dipyrone (metamizole), acting through its main metabolites 4-methyl-amino-antipyrine and 4-amino-antipyrine, has established analgesic, antipyretic, and spasmolytic pharmacological effects, which are mediated by poorly known mechanisms. In rats, intravenously administered dipyrone delays gastric emptying (GE) of liquids with the participation of capsaicin-sensitive afferent fibers. This effect seems to be mediated by norepinephrine originating from the sympathetic nervous system but not from the superior celiac-mesenteric ganglion complex, which activates ß2-adrenoceptors. In rats, in contrast to nonselective non-hormonal anti-inflammatory drugs, dipyrone protects the gastric mucosa attenuating the development of gastric ulcers induced by a number of agents. Clinically, it has been demonstrated that dipyrone is effective in the control of colic-like abdominal pain originating from the biliary and intestinal tracts. Since studies in humans and animals have demonstrated the presence of ß2-adrenoceptors in biliary tract smooth muscle and ß2-adrenoceptor activation has been shown to occur in dipyrone-induced delayed GE, it is likely that this kind of receptors may participate in the reduction of smooth muscle spasm of the sphincter of Oddi induced by dipyrone. There is no evidence that dipyrone may interfere with small bowel and colon motility, and the clinical results of its therapeutic use in intestinal colic appear to be due to its analgesic effect.

Effect of 4-aminoantipyrine on gastric compliance and liquid emptying in rats.

Dipyrone (Dp) delays gastric emptying (GE) in rats. There is no information about whether 4-aminoantipyrine (AA), one of its metabolites, has the same effect. The objectives of the present study were to assess the effects of AA and Dp on GE when administered intravenously (iv) and intracerebroventricularly (icv) (240 micromol/kg and 4 micromol/animal, respectively) and on gastric compliance when administered iv (240 micromol/kg). GE was determined in male Wistar rats weighing 250-300 g (5-10 per group) after icv or iv injection of the drug by measuring percent gastric retention (GR) of a saline meal labeled with phenol red 10 min after administration by gavage. Gastric compliance was estimated in anesthetized rats (10-11 per group), with the construction of volume-pressure curves during intragastric infusion of a saline meal. Compliance was significantly greater in animals receiving Dp (mean +/- SEM = 0.26 +/- 0.009 mL/mmHg) and AA (0.24 +/- 0.012 mL/mmHg) than in controls (0.19 +/- 0.009 mL/mmHg). AA and Dp administered iv significantly increased GR (64.4 +/- 2.5 and 54.3 +/- 3.8%, respectively) compared to control (34 +/- 2.2%), a phenomenon observed only with Dp after icv administration. Subdiaphragmatic vagotomy reduced the effect of AA (GR = 31.4 +/- 1.5%) compared to sham-treated animals. Baclofen, a GABAB receptor agonist, administered icv significantly reduced the effect of AA (GR = 28.1 +/- 1.3%). We conclude that Dp and AA increased gastric compliance and AA delayed GE, with the participation of the vagus nerve, through a pathway that does not involve a direct action of the drug on the central nervous system.

Dipyrone in association with atropine inhibits the effect on gastric emptying induced by hypoglycemia in rats.

Atropine (AT) and dipyrone (Dp) induce a delay of gastric emptying (GE) of liquids in rats by inhibiting muscarinic receptors and activating ß2-adrenergic receptors, respectively. The objective of the present study was to determine the effects of pretreatment with AT and Dp, given alone or in combination, on the effect of hypoglycemia in the liquid GE in rats. Male Wistar adult rats (280-310 g) were pretreated intravenously with AT, Dp, AT plus Dp or their vehicle and then treated 30 min later with iv insulin or its vehicle (n=8-10 animals/group). Thirty min after treatment, GE was evaluated by determining, in awake rats, the percent gastric retention (%GR) of a saline meal labeled with phenol red administered by gavage. The results indicated that insulin induced hypoglycemia in a dose-dependent manner resulting in a significant reduction in %GR of liquid only at the highest dose tested (1 U/kg). Pretreatment with AT significantly increased %GR in the rats treated with 1 U/kg insulin. Surprisingly, after pretreatment with AT, the group treated with the lowest dose of insulin (0.25 U/kg) displayed significantly lower %GR compared to its control (vehicle-treated group), which was not seen in the non-pretreated animals. Pretreatment with Dp alone at the dose of 40 mg/kg induced an increase in %GR in both vehicle and 0.25 U/kg-treated rats. A higher dose of Dp alone (80 mg/kg) significantly reduced the effect of a marked hypoglycemia induced by 1 U/kg of insulin on GE while in combination with AT the effect was completely abolished. The results with AT suggest that moderate hypoglycemia may render the inhibitory mechanisms of GE ineffective while Dp alone and in combination with AT significantly overcame the effect of hypoglycemia on GE.

Effect of antipyrine on the gastric emptying of liquid in rats.

Antipyrine (At) and dipyrone (Dp) delay gastric emptying (GE) in rats. The objective of the present study was to assess the effects of intravenous (iv) and intracerebroventricular (icv) administration of At and Dp on the GE of liquid by rats. GE was assessed in male Wistar rats (5-10 in each group) 10 min after the icv or iv drug injection by measuring percent gastric retention (%GR) of a saline test meal labeled with phenol red 10 min after administration by gavage. The At iv group was significantly higher (64.4 +/- 2.6%) compared to control (33.4 +/- 1.5%) but did not differ from the Dp group (54.3 +/- 3.8%). After icv administration of At, %GR (34.2 +/- 2%) did not differ from control (32.6 +/- 1.9%), but was significantly higher after Dp (54.5 +/- 2.3%). Subdiaphragmatic vagotomy significantly reduced %GR in the At group (30.2 +/- 0.7%) compared to the sham group, but was significantly higher than in the controls (23.0 +/- 0.5%). In the animals treated with At iv, baclofen significantly reduced %GR (28.3 +/- 2.4%) compared to vehicle-treated animals (55.2 +/- 3.2%). The same occurred in the animals treated iv with vehicle and icv with baclofen. Although vagotomy and baclofen reduced %GR per se, the reduction was twice more marked in the animals treated with At. The results suggest that At administered iv, but not icv, delays GE of liquid in rats with the participation, at least in part, of the vagus nerve and that this phenomenon is blocked by the activation of GABA B receptors in the central nervous system.

Effect of selective ß-adrenoceptor blockade and surgical resection of the celiac-superior mesenteric ganglion complex on delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats.

There is evidence for participation of peripheral ß-adrenoceptors in delayed liquid gastric emptying (GE) induced in rats by dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At). The present study aimed to determine whether ß-adrenoceptors are involved in delayed GE induced by phenylpyrazole derivatives and the role of the prevertebral sympathetic nervous system in this condition. Male Wistar rats weighing 220-280 g were used in the study. In the first experiment rats were intravenously pretreated with vehicle (V), atenolol 30 mg/kg (ATE, ß1-adrenergic antagonist), or butoxamine 25 mg/kg (BUT, ß2-adrenergic antagonist). In the second experiment, rats were pretreated with V or SR59230A 2 mg/kg (SRA, ß3-adrenergic antagonist). In the third experiment, rats were subjected to surgical resection of the celiac-superior mesenteric ganglion complex or to sham surgery. The groups were intravenously treated with saline (S), 240 µmol/kg Dp, AA, or At, 15 min after pretreatment with the antagonists or V and nine days after surgery. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. The %GR (means±SE, n=6) values indicated that BUT abolished the effect of Dp (BUT+Dp vs V+Dp: 35.0%±5.1% vs 56.4%±2.7%) and At (BUT+At vs V+At: 33.5%±4.7% vs 52.9%±2.6%) on GE, and significantly reduced (P<0.05) the effect of AA (BUT+AA vs V+AA: 48.0%±5.0% vs 65.2%±3.8%). ATE, SRA, and sympathectomy did not modify the effects of treatments. These results suggest that ß2-adrenoceptor activation occurred in delayed liquid gastric emptying induced by the phenylpyrazole derivatives dipyrone, 4-aminoantipyrine, and antipyrine. Additionally, the released neurotransmitter did not originate in the celiac-superior mesenteric ganglion complex.

Effect of the GABAB agonist baclofen on dipyrone-induced delayed gastric emptying in rats.

Dipyrone administered intravenously (iv) or intracerebroventricularly (icv) delays gastric emptying (GE) in rats. Gamma-aminobutyric acid (GABA) is the most potent inhibitory neurotransmitter of the central nervous system. The objective of the present study was to determine the effect of icv baclofen, a GABAB receptor agonist, on delayed GE induced by dipyrone. Adult male Wistar rats received a saline test meal containing phenol red as a marker. GE was indirectly evaluated by determining the percent of gastric retention (%GR) of the meal 10 min after orogastric administration. In the first experiment, the animals were injected iv with vehicle (Civ) or 80 mg/kg (240 micromol/kg) dipyrone (Dpiv), followed by icv injection of 10 microl vehicle (bac0), or 0.5 (bac0.5), 1 (bac1) or 2 microg (bac2) baclofen. In the second experiment, the animals were injected icv with 5 microl vehicle (Cicv) or an equal volume of a solution containing 4 micromol (1333.2 microg) dipyrone (Dpicv), followed by 5 microl vehicle (bac0) or 1 microg baclofen (bac1). GE was determined 10 min after icv injection. There was no significant difference between control animals from one experiment to another concerning GR values. Baclofen at the doses of 1 and 2 microg significantly reduced mean %GR induced by iv dipyrone (Dpivbac1 = 35.9% and Dpivbac2 = 26.9% vs Dpivbac0 = 51.8%). Similarly, baclofen significantly reduced the effect of dipyrone injected icv (mean %GR: Dpicvbac1 = 30.4% vs Dpicvbac0 = 54.2%). The present results suggest that dipyrone induces delayed GE through a route in the central nervous system that is blocked by the activation of GABAB receptors.

Effect of bacterial lipopolysaccharide on gastric emptying of liquids in rats.

The objectives of the present investigation were 1) to study the effect of bacterial lipopolysaccharide (LPS) on rat gastric emptying (GE) and 2) to investigate a possible involvement of the vagus nerve in the gastric action of LPS. Endotoxin from E. coli (strain 055:B5) was administered sc, ip or iv to male Wistar rats (220-280 g body weight) at a maximum dose of 50 micrograms/kg animal weight. Control animals received an equivalent volume of sterile saline solution. At a given time period after LPS administration, GE was evaluated by measuring gastric retention 10 min after the orogastric infusion of a test meal (2 ml/100 g animal weight), which consisted of 0.9% NaCl plus the marker phenol red (6 mg/dl). One group of animals was subjected to bilateral subdiaphragmatic vagotomy or sham operation 15 days before the test. A significant delay in GE of the test meal was observed 5 h after iv administration of the endotoxin at the dose of 50 micrograms/kg animal weight. The LPS-induced delay of GE was detected as early as 30 min and up to 8 h after endotoxin administration. The use of different doses of LPS ranging from 5 to 50 micrograms/kg animal weight showed that the alteration of GE was dose dependent. In addition, vagotomized animals receiving LPS displayed a GE that was not significantly different from that of the sham control group. However, a participation of the vagus nerve in LPS-induced delay in GE could not be clearly demonstrated by these experiments since vagotomy itself induced changes in this gastric parameter. The present study provides a suitable model for identifying the mechanisms underlying the effects of LPS on gastric emptying.

Gastric emptying of liquids in rats dehydrated by water deprivation.

The gastric emptying of liquids was investigated in male Wistar rats (8 to 10 weeks old, 210-300 g) dehydrated by water deprivation. In this model of dehydration, weight loss, hematocrit and plasma density were significantly higher in the dehydrated animals than in the control groups after 48 and 72 h of water deprivation (P < 0.05). Three test meals (saline (N = 10), water (N = 10) and a WHO rehydrating solution containing in one liter 90 mEq sodium, 20 mEq potassium, 80 mEq chloride and 30 mEq citrate (N = 10)) were used to study gastric emptying following water deprivation for 24, 48 and 72 h. After 72 h, gastric emptying of the water (39.4% retention) and rehydrating solution (49.2% retention) test meals was significantly retarded compared to the corresponding control groups (P < 0.05, Mann-Whitney test). The 72-h period of deprivation was used to study the recovery from dehydration, and water was supplied for 60 or 120 min after 67 h of deprivation. Body weight loss, hematocrit and plasma density tended to return to normal when water was offered for 120 min. In the animals supplied with water for 60 min, there was a recovery in the gastric emptying of water while the gastric emptying of the rehydrating solution was still retarded (53.1% retention; P < 0.02, Kruskal-Wallis test). In the group supplied with water for 120 min, the gastric emptying of the rehydrating (51.7% retention) and gluco-saline (46.0% retention) solutions tended to be retarded (P = 0.04, Kruskal-Wallis test). In this model of dehydration caused by water deprivation, with little alteration in the body electrolyte content, gastric emptying of the rehydrating solution was retarded after rehydration with water. We conclude that the mechanisms whereby receptors in the duodenal mucosa can modify gastric motility are altered during dehydration caused by water deprivation.

Effect of Phoneutria nigriventer spider venom on gastric emptying in rats.

The effect of Phoneutria nigriventer spider venom (PNV) on the gastric emptying of liquids was studied in 240 young adult Wistar rats (2-3 months of age) divided into subgroups of 8 animals each. The study was performed in 3 stages. Initially, PNV was injected into rats at doses of 0.19, 0.38 or 0.76 mg/kg and the effect on gastric emptying was assessed 30 min later. In the second stage, a time-course study was performed by injecting 0.76 mg PNV/kg and measuring the effect on gastric emptying 15, 60 and 120 min post-venom. In the last stage, in order to investigate the possible mechanisms of PNV influence on gastric emptying, one group of rats underwent subdiaphragmatic vagotomy and then received 0.76 mg PNV/kg while three other groups were pretreated iv with either prazosin (0.4 mg/kg), domperidone (1.0 mg/kg) or propranolol (0.6 mg/kg) and then given 0.38 or 0.76 mg PNV/kg. In this last stage, gastric retention was measured 30 min post-venom. Each animal received a saline test meal solution containing phenol red as a marker (60 micrograms/ml). Ten min after administering the test meal by gavage, gastric retention was determined by measuring the residual test meal marker concentration and the animals were sacrified. PNV (0.76 mg/kg) provoked a significant delay in gastric emptying of liquids 15, 30 and 60 min after its administration. Propranolol partially interfered with gastric emptying in rats that had received 0.38 and 0.76 mg PNV/kg. Vagotomy and pretreatment of the rats with prazosin and domperidone had no effect. We conclude that the delay in the liquid gastric emptying observed in severely envenomed rats was probably due, at least in part, to a venom-stimulated release of catecholamines which inhibited gastric motility by activating smooth muscle beta-adrenergic receptors.

Gastric emptying in rats with acetaminophen-induced hepatitis.

The objective of this work was to study the gastric emptying (GE) of liquids in fasted and sucrose-fed rats with toxic hepatitis induced by acetaminophen. The GE of three test meals (saline, glucose and mayonnaise) was evaluated in Wistar rats. For each meal, the animals were divided into two groups (N = 24 each). Group I was fed a sucrose diet throughout the experiment (66 h) while group II was fasted. Forty-two hours after the start of the experiment, each group was divided into two subgroups (N = 12 each). Subgroup A received a placebo and subgroup B was given acetaminophen (1 g/kg). Twenty-four hours later, the GE of the three test meals was assessed and blood samples were collected to measure the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and acetaminophen. In group IB, the mean AST and ALT values were 515 and 263 IU/l, respectively, while for group IIB they were 4014 and 2472 IU/l, respectively. The mean serum acetaminophen levels were higher in group IIB (120 micrograms/ml) than in group IB (87 micrograms/ml). The gastric retention values were significantly higher in group IIB than in group IIA for all three test meals: saline, 51 vs 35%; glucose, 52 vs 38% and mayonnaise, 51 vs 29% (median values). The correlation between gastric retention and AST levels was significant (P < 0.05) for group IIB for the three test meals: r = 0.73, 0.67 and 0.68 for saline, glucose and mayonnaise, respectively. We conclude that GE is altered in rats with hepatic lesions induced by acetaminophen, and that these alterations may be related to the liver cell necrosis caused by the drug.

The effect of bacterial lipopolysaccharide on gastric emptying in rats suffering from moderate renal insufficiency.

The objective of the present study was to evaluate the response of rats suffering from moderate renal insufficiency to bacterial lipopolysaccharide (LPS, or endotoxin). The study involved 48 eight-week-old male SPF Wistar rats (175-220 g) divided into two groups of 24 animals each. One group underwent 5/6 nephrectomy while the other was sham-operated. Two weeks after surgery, the animals were further divided into two subgroups of 12 animals each and were fasted for 20 h but with access to water ad libitum. One nephrectomized and one sham-treated subgroup received E. coli LPS (25 micrograms/kg, i.v.) while the other received a sterile, pyrogen-free saline solution. Gastric retention (GR) was determined 10 min after the orogastric infusion of a standard saline test meal labeled with phenol red (6 mg/dl). The gastric emptying of the saline test meal was studied after 2 h. Renal function was evaluated by measuring the plasma levels of urea and creatinine. The levels of urea and creatinine in 5/6 nephrectomized animals were two-fold higher than those observed in the sham-operated rats. Although renal insufficiency did not change gastric emptying (median %GR = 26.6 for the nephrectomized subgroup and 29.3 for the sham subgroup), LPS significantly retarded the gastric emptying of the sham and nephretomized groups (median %GR = 42.0 and 61.0, respectively), and was significantly greater (p < 0.01) in the nephrectomized rats. We conclude that gastric emptying in animals suffering from moderate renal insufficiency is more sensitive to the action of LPS than in sham animals.

Effects of adrenalectomy and adrenal enucleation on liquid gastric emptying in rats.

The effects of adrenalectomy and adrenal enucleation on liquid gastric emptying were studied in male Wistar rats that were adrenalectomized, adrenal enucleated (AE) or sham operated (SH). The animals in the first group had free access to a 1% NaCl solution (ADS), while the animals in the second and third groups were divided into two subgroups, which ingested either tap water (AEW, SHW) or 1% NaCl solution (AES, SHS). The gastric emptying study was performed on the 16th post-operative day. Three test meals labeled with phenol red (6 mg/dl) were used (0.9% NaCl, 1.8% NaCl and 5% glucose). Percent gastric retention was determined 10 min after orogastric infusion of the NaCl test meals and 15 min after the glucose meal. Gastric retention of the ADS subgroup was significantly lower (P<0. 01) (median = 19.8% vs 25.5% for SHW, vs 31.9% for SHS, vs 25.7% for AEW, and vs 27.1% for AES) for the 0.9% NaCl test meal and for the 1. 8% NaCl test meal (33.5% for ADS vs 47.5% for AEW and 50.6% for AES). When 5% glucose was used as a test meal, gastric retention was similar for all subgroups. These results suggest that ablation of the adrenal cortex results in increased gastric emptying of an isosmolar NaCl meal.

Evidence of the effect of dipyrone on the central nervous system as a determinant of delayed gastric emptying observed in rats after its administration.

Dipyrone administered intravenously (iv) delays gastric emptying (GE) in rats. The objectives of the present study were to assess: 1) the effect of the dose of dipyrone and time after its iv administration on GE in rats, 2) the effect of subdiaphragmatic vagotomy (VgX) and bilateral electrolytic lesion of the paraventricular nucleus (PVNX) on the delayed GE induced by the drug, and 3) the intracerebroventricular (icv) action of dipyrone and of one of its metabolites, 4-aminoantipyrine on GE. Male Wistar rats received saline labeled with phenol red intragastrically as a test meal. GE was indirectly assessed by the determination of percent gastric retention (GR) of the test meal 10 min after administration by gavage. Dipyrone delays GE in a dose- and time-dependent manner. Thirty minutes after the iv administration of 80 mg/kg dipyrone, the animals showed significantly higher GR (mean = 62.6%) compared to those receiving vehicle (31.5%). VgX and PVNX significantly reduced the iv effect of 80 mg/kg dipyrone (mean %GR: VgX = 28.3 vs Sham = 55.5 and PVNX = 34.5 vs Sham = 52.2). Icv administration of 4 mol dipyrone caused a significant increase in GR (54.1%) of the test meal 10 min later, whereas administration of 4 mol 4-aminoantipyrine had no effect (34.4%). Although the dipyrone dose administered icv was 16 times lower than that applied iv, for the same time of action (10 min), the GR of animals that received the drug icv (54.1%) or iv (54.5%) did not differ significantly. In conclusion, the present results suggest that the effect of dipyrone in delaying GE is due to the action of the drug on the central nervous system, with the participation of the PVN and of the vagus nerve.

Gastric emptying of a liquid meal in experimental chemical pneumonitis.

Gastric emptying of a liquid test meal was studied in an experimental model of chemical pneumonitis. In the first phase, 160 microliters of a hydrocarbon mixture was injected iv into 10 young adult rats, and the same volume of saline solution was injected into 10 controls. Arterial blood gases and lung dry and wet weight were determined. In the second phase, gastric emptying of a 5% (w/v) glucose solution marked with phenol red (6 mg/dl) was studied 5, 10, 20 and 30 min after orogastric infusion of the test meal. Gastric retention was determined by measuring the concentration of the marker in the residual test meal recovered from the stomach after killing the animal. Thirty-two experimental and 32 control animals were paired and eight pairs were used at each time. The wet weight and external volume of the lungs were determined in all animals and 20 experimental animals were analyzed histopathologically. The animals of the experimental group developed intense macro- and microscopic pulmonary alterations. PaO2 values (mean +/- SD) at the first (70.7 +/- 5.9 mmHg) and fifth hour (71.1 +/- 8.5 mmHg) were significantly lower than the respective values obtained for the control group (109.5 +/- 13.5 and 113.9 +/- 11.2 mmHg). Gastric retention at 5, 10, 20 and 30 min was significantly higher in animals with pneumonitis (median: 59.1%, 55.4%, 45.3%, 27.2%) when compared to respective values for the control group (median: 47.5%, 46.6%, 24.1%, 19.3%). These results indicate a delay in the gastric emptying of liquids in serious pulmonary disorders.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic lactose intake modifies the gastric emptying of monosaccharides but not of disaccharides in weanling rats.

Ninety-six weanling male Wistar rats were fed for four weeks one of two different chows: a normal rat chow containing 55.5% (w/w) starch (control group, N = 48) or a rat chow in which starch was partially replaced by lactose, in such a way that the experimental group (N = 48) received 35.5% (w/w) starch and 20% (w/w) lactose. The gastric emptying of fluid was then studied by measuring the gastric retention of four test meals containing lactose (5% or 10%, w/v) or glucose+galactose (5% or 10%, w/v). Homogenates of the small intestine were assayed for lactase activity. The gastric retention values were obtained 15 min after orogastric infusion of the liquid meals. The median values for gastric retention of the 5% lactose solutions were 37.7% for the control group and 37.0% for the experimental group (P > 0.02). For the 10% lactose solution the median values were 51.2% and 47.9% (P > 0.02) for the control and experimental groups, respectively. However, for the 2.5% glucose +2.5% galactose meal the median gastric retention was lower (P < 0.02) in the group fed a lactose-enriched chow (38.5%) than in the control group (41.6%). For the 5% glucose +5% galactose solution the median values were not statistically different between groups, 65.0% for the control group and 58.8% for the experimental group. The median values of the specific lactase activity in the small intestine homogenate was 0.74 U/g in the control group and 0.91 U/g in the experimental group. These values were not statistically different (P > 0.05). These results suggest that the prolonged ingestion of lactose by young adult rats changes the gastric emptying of a solution containing 5% monosaccharides. This adaptation may reflect the desensitization of intestinal nutrient receptors, possibly by an osmotic effect of lactose present in the chow.

Faster gastric emptying of a liquid meal in rats after hypothalamic dorsomedial nucleus lesion.

The effects of dorsomedial hypothalamic (DMH) nucleus lesion on body weight, plasma glucose levels, and the gastric emptying of a liquid meal were investigated in male Wistar rats (170-250 g). DMH lesions were produced stereotaxically by delivering a 2.0-mA current for 20 s through nichrome electrodes (0.3-mm tip exposure). In a second set of experiments, the DMH and the ventromedial hypothalamic (VMH) nucleus were lesioned with a 1.0-mA current for 10 s (0.1-mm tip exposure). The medial hypothalamus (MH) was also lesioned separately using a nichrome electrode (0.3-mm tip exposure) with a 2.0-mA current for 20 s. Gastric emptying was measured following the orogastric infusion of a liquid test meal consisting of physiological saline (0.9% NaCl, w/v) plus phenol red dye (6 mg/dl) as a marker. Plasma glucose levels were determined after an 18-h fast before the lesion and on the 7th and 15th postoperative day. Body weight was determined before lesioning and before sacrificing the rats. The DMH-lesioned rats showed a significantly faster (P < 0.05) gastric emptying (24.7% gastric retention, N = 11) than control (33.0% gastric retention, N = 8) and sham-lesioned (33.5% gastric retention, N = 12) rats, with a transient hypoglycemia on the 7th postoperative day which returned to normal by the 15th postoperative day. In all cases, weight gain was slower among lesioned rats. Additional experiments using a smaller current to induce lesions confirmed that DMH-lesioned rats had a faster gastric emptying (25.1% gastric retention, N = 7) than control (33.4% gastric retention, N = 17) and VMH-lesioned (34.6% gastric retention, N = 7) rats. MH lesions resulted in an even slower gastric emptying (43.7% gastric retention, N = 7) than in the latter two groups. We conclude that although DMH lesions reduce weight gain, they do not produce consistent changes in plasma glucose levels. These lesions also promote faster gastric emptying of an inert liquid meal, thus suggesting a role for the DMH in the regulation of gastric motility.

Correlation between the severity of acute hepatic necrosis induced by acetaminophen and serum aminotransferase levels in fasted and sucrose-fed rats.

The relationship between serum aminotransferase levels and the acute hepatic necrosis induced by acetaminophen was studied in 24 male Wistar rats (220-265 g). The animals were divided into two groups, one of which was fasted for 66 h (group I) while the other was fed only sucrose cubes ad libitum (group II). The animals received I g acetaminophen per kg body weight 42 h after the onset of the experiment. Twenty-four hours later, blood was drawn to measure aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and the liver was removed for both macro- and microscopic examination. The intensity of the hepatic necrosis was scored according to the extent of the lesion. The hepatic necrosis was more frequent and intense in group I, with the aminotransferase levels being higher in this group (median AST and ALT levels were 3900 IU/l and 2511 IU/l, respectively, for group I and 119 IU/l and 79 IU/l, respectively, for group II). There was a positive correlation (rs) between the intensity of hepatic necrosis assessed microscopically and the levels of AST (group I, rs = 0.83; group II, rs = 0.79) and ALT (group I, rs = 0.58; group II, rs = 0.80). These findings suggest that aminotransferase levels are a reliable indicator of the degree of hepatic necrosis in this model of acetaminophen intoxication.

Gastric emptying of maltose, sucrose, lactose and lactulose in rats with ontogenic lactase deficiency.

The gastric emptying of maltose, sucrose, lactose and lactulose was compared in young adult rats with ontogenic lactase deficiency. Eight animals were employed for each sugar meal at each time of study (total number of animals = 192). Each animal received a test meal consisting of a solution of the sugar (100 mg/ml) and phenol red as marker and gastric retention was measured at 5, 10, 20, 30, 45 and 60 min after orogastric infusion of the test meal. Gastric retention was determined by measuring the concentration of the marker in the residual test meal recovered from the stomach after killing the animal. There was no difference between the gastric emptying of lactose and lactulose. The gastric emptying of maltose was significantly slower during the initial 30 min and the emptying of sucrose was identical to that of maltose only at 5 min and could not be distinguished from that of lactose and lactulose at later times. These data support the observation, made in human subjects, that, under conditions of ontogenic lactase deficiency, the modulation of gastric emptying of lactose is ineffective. It is possible that the rapid emptying of sucrose is due to the saturation of sucrase because of substrate overload which impairs the intestinal inhibitory control of gastric emptying.

Effect of toxin-g from Tityus serrulatus scorpion venom on gastric emptying in rats.

The effect of toxin-gamma from Tityus serrulatus scorpion venom on the gastric emptying of liquids was studied in 176 young adult male Wistar rats (2-3 months of age) divided into subgroups of 8 animals each. Toxin-gamma was injected i.v. at doses of 25, 37.5, 50 or 100 micrograms/kg and the effect on gastric emptying was assessed 30 min and 8 h later. A time-course study was also performed by injecting 50 micrograms of toxin-gamma/kg and measuring the effect on gastric emptying at times 0.25, 0.5, 1, 2, 4, 8, 24 and 48 h post-venom. Each envenomed animal was paired with its saline control and all received a saline test meal solution containing phenol red (60 micrograms/ml) as a marker. Ten minutes after administering the test meal by gavage the animals were sacrificed and gastric retention was determined by measuring the residual marker concentration of the test meal. A significant delay in gastric emptying, at 30 min and 8 h post-venom, was observed only after 50 and 100 micrograms of toxin-gamma/kg compared to control values. The responses to these two doses were significantly different after 8 h post-venom. Toxin-gamma (50 micrograms/kg) significantly delayed the gastric emptying of liquids at all times studied, with a peak response at 4 h after toxin administration compared to control values. These results indicate that the i.v. injection of toxin-gamma may induce a rapid, intense and sustained inhibition of gastric emptying 0.25 to 48 h after envenomation.

Effect of paraventricular nucleus lesion and cold restraint stress on gastric emptying of a liquid meal in rats.

The effects of cold restraint stress on gastric emptying (GE) and the involvement of the hypothalamic paraventricular nucleus (PVN) were investigated in male Wistar rats (200-250 g body weight). Electrolytic lesions were produced stereotaxically in the nucleus by passing a 2.0-mA current for 10 s through stainless steel electrodes. GE was measured by means of a liquid test meal of 5% (w/v) glucose solution plus phenol red (6 mg/dl) dye as marker, given by orogastric infusion. Cold restraint stress induces a significant increase (43.7%, N = 11) in gastric retention of a 5% glucose solution in rats, i.e., a delay in GE of this solution. However, restraint stress alone does not produce any change. Both truncal vagotomy and electrolytic lesion of the PVN completely block the cold restraint-induced delay in GE. However, PVN lesion per se results in a decrease of GE (30.6%, N = 10) when compared to nonoperated controls. In addition, PVN-lesioned rats exposed to cold restraint present a slightly faster GE (14.7%, N = 11) than controls, demonstrating an opposite response to that initially observed without lesion. These data suggest an important role for PVN efferents, probably influencing medullary vagal preganglionic neurons, in the development of this gastric motor impairment under stress conditions.