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1. Acute galactosamine (Gal) hepatitis was induced in rats drinking ad libitum either sodic bicarbonated water of Vichy Grande Grille (GG) or ordinary tap water (OH2). Two series of experiments were performed. 2. In the first series, Gal-induced hepatitis was moderate. Twenty four hours after IP Gal injection, GG treated rats had relative to OH2 treated rats a decrease of bile flow and BSP excretion, and an increase of serum transaminase and bilirubin. Seven days after Gal the liver had returned to normal except for an increase in biliary bilirubin and liver total lipids. 3. In the second series, Gal-induced hepatitis was severe. Twenty four hours after galactosamine administration, an increase in mortality after anesthesia was found in Gal/GG rats. An increase of liver size and total hepatic lipids was also observed, while bile secretion, BSP excretion, cyt P 450 and ARN decreased in Gal/GG rats. Steatosis and inflammatory reactions were more important in Gal/GG than in Gal/OH2 rats. Most parameters came back to their normal levels in two days in Gal/OH2 rats, while 7 days were generally necessary in Gal/GG treated animals. Hepatic DNA kept increasing in Gal/GG animals and was still higher after 7 days, maybe due to a greater inflammatory reaction in the liver, maybe following a stimulated hepatocyte regenerative response. 4. These results indicate that GG water is not an inoffensive salt solution.

The effects of the drug CRL 40827 and salbutamol, a structurally related compound, on exocrine pancreatic secretion in acutely fistulized anaesthetized rats and in chronically fistulized conscious rats were studied. CRL 40827 and salbutamol (0.05-0.45 mumol/kg per min, for 2 h) increased the basal secretion of fluid and bicarbonate in anaesthetized rats. The effect of CRL 40827 (15% of the maximal effect of secretin) was suppressed by propranolol (a non-specific beta-adrenoceptor antagonist), by ICI 118551 (a beta 2-antagonist) and by atenolol (a beta 1-antagonist). The effect of salbutamol (25% of the maximal effect of secretin) was suppressed by propranolol and ICI 118551 but was only slightly decreased by atenolol. The stimulant peak effects of CRL 40827 and salbutamol on volume and bicarbonate output were additive to those of 2-deoxy-glucose whereas the effect of 2-deoxy-glucose on protein output was not changed by either drug. CRL 40827 and salbutamol decreased the basal interdigestive protein output in a dose-related manner in conscious rats. CRL 40827 was 27 times less potent than salbutamol. The pancreatic outputs of fluid, bicarbonate and protein after an intragastric meal were decreased by both drugs. However, only salbutamol significantly decreased the cumulative effect of the meal on protein output compared to basal output. These results suggest that the stimulant effect of salbutamol on the pancreatic secretion of fluid and bicarbonate depends mainly on beta 2-adrenoceptors whereas that of CRL 40827 involves adrenoceptors of an as yet undefined subtype.

The effects of pirenzepine and atropine on basal pancreatic exocrine secretion were studied in conscious rats fitted with a chronic pancreatic fistula. Pirenzepine was about 50 times less potent than atropine on a molar basis in inhibiting pancreatic secretion (respectively 44x for volume and 51x for protein output), while the efficacies of both drugs were in the same range. These results indicate that basal pancreatic secretion in vivo is mainly regulated by muscarinic mechanisms poorly sensitive to pirenzepine, and analogous to the M2 receptors described by others in vitro.

The aim of this study was to compare the stimulation of the external pancreatic secretion induced in rats by two glucose analogs: 5-thio-glucose (5-TG) and 2-deoxy-glucose (2-DG). In rats with an acute pancreatic fistula, 5-TG and 2-DG induced a dose-related increase in outputs of sodium (reflecting the volume), bicarbonate and total protein of the pancreatic juice. The efficacy of both drugs was not significantly different. Maximal responses were obtained with 75 mg/kg 5-TG and 225 mg/kg 2-DG and were approximately 3.5 x (sodium), 5 x (bicarbonate) and 8.5 x (protein) the basal level. Dose-response curves to 5-TG were shifted to the left with respect to 2-DG. The DE50 was approximately 25 mg/kg for 5-TG and 60 mg/kg for 2-DG. The molar potency ratio was 2.5 x, 3.1 x and 3.3 x in favor of 5-TG, for sodium, bicarbonate and protein respectively. The potency, but not the efficacy, of 5-TG is thus greater than that of 2-DG in stimulating external pancreatic secretion.

The effects of loperamide on exocrine pancreatic secretion were studied in rats fitted with chronic or acute fistulas. Intraduodenal injection of loperamide in conscious rats resulted in a dose-dependent inhibition of basal pancreatic secretion involving volume and bicarbonate and protein output with an ED50 of about 0.5 mg/kg. The maximal inhibition observed was about 60% for volume and bicarbonate output and 90% for protein output. Loperamide induced an inhibition of pancreatic secretion in conscious rats that was naloxone-sensitive and persisted in cimetidine-treated rats. Thus, it did not depend on modifications of gastric secretion. In anaesthetized rats, loperamide did not inhibit the pancreatic secretion evoked by agents acting directly on the pancreatic cells (acetylcholine, secretin, CCK) but it inhibited by 100% the pancreatic secretion induced by vagal electrical stimulation (VES) and by 80-100% that induced by 5 thio-glucose, a centrally acting vagal stimulatory agent. Loperamide inhibition of VES-induced pancreatic secretion was different from that obtained with morphine or methadone since these opiate drugs could only inhibit by 50-60% maximally the VES-stimulated pancreatic secretion. The loperamide inhibition of VES-induced secretion was naloxone-insensitive, while loperamide inhibition of 5 thio-glucose-induced secretion was in part naloxone-sensitive. These results suggest that loperamide exerts a potent inhibition of pancreatic secretion by acting on the nerve supply to the pancreas through both opiate and non-opiate mechanisms.

Two types of pancreatic fistulas were directly compared in Wistar rats, to define more accurately the differences between collecting pancreatic juice under anesthesia (acute fistula) and in awake restrained animals (chronic fistula). Basal outputs of water, bicarbonate and total protein were about then times larger in chronic than in acute animals; they could be larger than the maximal secretory rate in anaesthetized rats. As a corollary, the chronic preparation was less sensitive to ecbolic and hydrelatic stimulations, with respect to basal levels. It is concluded that chronic fistula rats display a highly stimulated state of pancreatic secretion, probably due to the potentiation of several neurohumoral factors. Whatever this stimulation originates from, it renders the model less suitable for studies on ancreatic stimulating agents. On the contrary, anaesthetized rats displayed a low secretion more responsive to stimulating agents.

Pancreatic secretion in anesthetized rats with acute fistulas was provoked by caerulein, acetylcholine, electrical stimulation of the vagus nerves or by 2-deoxy-D-glucose (2-DG). Venous infusions of norepinephrine, isoprenaline or dopamine inhibited the 2-DG-stimulated enzyme secretion but not that provoked by caerulein, acetylcholine or vagal electrical stimulation. Intracerebroventricular administration of norepinephrine or isoprenaline also inhibited 2-DG-stimulated enzyme secretion. It was confirmed that the amines stimulated water and electrolyte secretion by the pancreas in the order of potency isoprenaline greater than norepinephrine greater than dopamine. The results are consistent with a model whereby norepinephrine and isoprenaline exert their effect on pancreatic secretion via a central inhibition of vagal drive to the pancreas, together with a direct stimulating effect on water and electrolyte secretion at the level of pancreatic cells.

Human and rat GRFs have been reported to stimulate cAMP production and amylase release by guinea pig acinar cells in vitro, with different potencies. Previous reports indicated that hGRF had no effect on pancreatic secretion of the rat in vivo. In the present experiments, dose-response studies were made with rGRF, VIP and secretin on the pancreatic secretion of anaesthetized rats. All three peptides stimulated pancreatic secretion. rGRF induced a slight water and electrolyte secretion, with an efficacy about ten times smaller than secretin, and a potency about thirty times smaller. rGRF stimulated total protein output with the same efficacy as secretin and VIP, and with the same potency as VIP, that is about 100 times smaller than secretin. rGRF increased the concentration of total protein, but not that of bicarbonate in pancreatic juice. Maximal doses of VIP and rGRF did not show any additive effect. It is concluded that large doses of rGRF are able to stimulate the rat acinar cells in vivo, presumably through an interaction with VIP receptors.

The stimulatory effects of isoproterenol and secretin on external pancreatic secretion were compared in the rat. 1. In acute fistula, pylorus ligation, atropine, glucagon did not change either of the stimulated secretions. Propranolol inhibited isoproterenol-induced secretion and did not change secretin induced stimulation. Theophylline alone displayed a large hydrelatic stimulatory effect, without increasing protein excretion; the effect of theophylline was additive with the effects of isoproterenol or secretin but no evidence was found of potentiation or prolongation of action. Isoproterenol did not increase pancreatic blood flow and induced no variations in the plasma levels of immunoreactive secretin. Combining various doses of isoproterenol and secretin did not allow to reach secretory levels greater than the maximal response to secretin. 2. In conscious rats chronic fistulae, isoproterenol and secretin had a distinct effect.

The regenerating rat liver after partial hepatectomy was used as a model to study the effects of an hypolipidaemic drugs, tiadenol (bis hydroxyethylthio 1--10 decane). Seven days after partial hepatectomy, liver weight, DNA, RNA, total protein and cytochrome P-450 were increased in tiadenol treated rats, relative to hepatectomized controls. Tiadenol displaying similar effects on the intact liver, it is concluded that this hypolipidaemic drug maintains its hepatomegalic action on the regenerating rat liver.