Pancreatic response of anaesthetized and conscious rats to bolus injection of cholecystokinin-pancreozymin

Pancreatic secretion was studied in anaesthetized rats tested immediately after surgery or in conscious rats tested 48 hr after the cannulation of the pancreatic duct. Pancreatic flow, protein output and enzyme output were measured over a 30-min period in the unstimulated state and after the intravenous injection of bolus doses of cholecystokinin-pancreozymin (CCK-PZ) ranging from 1.25 to 20 Crick-Harper-Raper units (CHRU). Each animal received three doses of CCK-PZ, as either ascending or descending doses. In anaesthetized rats there was a linear relationship between the log-dose of CCK-PZ and the flow, protein and enzyme output with both the ascending and descending doses. In contrast, in conscious rats flow was unaffected by CCK-PZ, and protein output was greatest after the first dose, whether this was given in the ascending or descending doses. At all CCK-PZ levels flow in anaesthetized rats was less than that seen in conscious animals, but at doses of CCK-PZ above 5.00 CHRU protein output was greater in anaesthetized rats than in conscious rats. Ultrastructural studies of the pancreas showed areas of focal cytoplasmic degeneration and possible blockage of the duct with cellular debris after administration of high doses of CCK-PZ to conscious rats. These changes may be responsible for the reduced protein output with the second and third dose of CCK-PZ in these animals. No such changes were seen in anaesthetized rats after similar doses of CCK-PZ. These studies show fundamental differences in the response of the pancreas to CCK-PZ in anaesthetized and conscious rats. The mechanism for this difference is not clear, but it may represent a change in the normal response to CCK-PZ in the anaesthetized rats as a result of the effects of acute operative trauma, possibly acting through changes in pancreatic blood flow.     

The effect of pentosan polysulphate (SP54) on the fibrinolytic enzyme system. An experimental animal study

Pentosan polysulphate (SP54) causes a transient increase in blood fibrinolysis in conscious and anaesthetized rats. Postoperative "fibrinolytic shutdown" was prevented by a dose of 2 mg/kg body weight but there appeared to be no dose-response relationship with higher doses. Fibrinolysis was also measured in conscious unstressed animals using an indwelling jugular cannula. The venous response to SP54 in these animals was substantially higher than the arterial response. Experiments with an inferior vena cava model of thrombosis suggest that a single dose of 10 mg/kg pentosan polysulphate given 90 min after thrombus formation is sufficient to achieve thrombolysis. This effect was more marked if the animals were given multiple doses over 24 to 48 hours.     

Caerulein-induced acute pancreatitis in the rat. Pancreatic secretory response to cholecystokinin.

The response of pancreatic exocrine secretion to cholecystokinin (CCK), has been studied in experimental acute pancreatitis induced in rats by supramaximal doses of caerulein. Several doses of caerulein were used (4, 20 and 40 micrograms/Kg) and each one was administered by four subcutaneous injections over 3 h at hourly intervals. Pancreatic juice was collected 9 h after the first injection. The caerulein-treated animals showed a statistically significant increase in serum amylase levels. Secretory activity of ductular cells remained unchanged in all the caerulein-treated animals, but total protein and amylase secretion decreased significantly at all the caerulein doses used, both in resting conditions and under stimulation with CCK (1.25 micrograms/Kg/h). Despite this the acinar cells of rats treated with the lowest dose of caerulein retained a certain degree of secretory function since amylase activity in pancreatic juice was greater than in other groups of rats treated with higher doses of caerulein. Moreover, the percentage of increase observed in total protein and amylase in response to CCK respect to basal secretion is similar to that of the untreated animals. At higher doses (20 and 40 micrograms/Kg) the secretory capacity in response to CCK was inhibited. Therefore CCK administration in slight acute pancreatitis could be used as a therapy since it favours the secretion of pancreatic enzymes at percentual levels similar to those of the controls.     

Effect of exogenous and endogenous insulin on the secretory response of the pancreas to the octapeptide of cholecystokinin (CCK8) in normal rats

The author studied the effect of insulin on CCK8-stimulated secretion by the pancreas. CCK8 (0.6 nmol.kg-1) was administered to normal anaesthetized rats 30 min after the intravenous injection of insulin (10 U.kg-1), glucose (2 g.kg-1) or NaCl (controls). Pancreatic juice was collected from the intubated common bile duct. In rats given exogenous insulin, there were no statistically significant differences in total protein, amylase and trypsinogen output after CCK8 compared with the controls. In rats in which endogenous insulin secretion was stimulated with glucose, the amylase response to CCK8 was not significantly different from the control animals, but the trypsinogen response was significantly lower. The results show that insulin, in some still unknown manner, inhibits the trypsinogen secretory response to CCK8. In addition, they confirm data claiming that the synthesis and secretion of pancreatic amylase require a given critical ratio of insulin to glucose, or of insulin to the factor stimulating pancreatic secretion.     

Effects of selective cholecystokinin antagonists L364,718 and L365,260 on food intake in rats

The selective type A and B cholecystokinin (CCK) receptor antagonists L364,718 and L365,260 were used to identify the receptor subtype that mediates the satiety effect of endogenous CCK. Male rats (n = 12–13/group), fed ground rat chow ad lib, received L364,718 (0, 1, 10, 100, or 1000 μg/kg IP) or L365,260 (0, 0.1, 1, 10, 100, 1000, or 10,000 μg/kg IP) 2 h after lights off, and food intake was measured 1.5, 3.5, and 5.5 h later. L364,718 significantly stimulated 1.5-h food intake by more than 40% at 10 μg/kg and higher doses; cumulative intake at 3.5 and 5.5 h remained elevated by about 20% at 1000 and 100 μg/kg of L364,718, respectively. In contrast, L365,260 had no significant stimulatory effect on feeding at any dose. The potency of L365,260 for antagonizing gastrin-stimulated gastric acid secretion was examined in unanesthetized rats. Male rats (n = 14), prepared with gastric and jugular vein cannulas, received doubling doses of gastrin (G-17I) (0.16–5 nmol/kg/h IV), each dose for 30 min, and gastric juice was collected for each 30-min period. G-17I stimulated gastric acid output dose dependently; the minimal effective dose was 0.16 nmol/kg/h, while maximal output (5-fold above basal) occurred at 5 nmol/kg/h. L365,260 (0, 1, 10, 100, 1000, or 10,000 μg/kg IV), administered 30 min before continuous infusion of G-17I (1.25 or 5 nmol/kg/h), significantly inhibited acid output only at 10,000 μg/kg; cumulative 60-min output was decreased by 60%. These results suggest that CCK acts at CCK-A receptors to produce satiety during the dark period in ad lib-feeding rats.     

Effects of pancreatic polypeptide on the pancreatic exocrine secretion stimulated by secretin and cholecystokinin in the conscious pig

Fourteen castrated male Large White pigs, weighing 42.5 +/- 1.0 kg, were fitted with pancreatic and duodenal fistulae for pancreatic secretion studies. Moreover, catheters were placed in a carotid artery for blood sampling and in a jugular vein for peptide infusion. Pancreatic juice was automatically restituted to the animals and continuously sampled for analysis on experimental days. Following an 8-day recovery period, perfusion studies were performed after an overnight fast. After a 30-min basal period, sustained pancreatic flow and protein output were obtained and maintained throughout the assay with secretin (36 pmol/kg/h) and CCK-8 (600 pmol/kg/h) infusion. Then, 200, 400, 600, 800 or 1200 pmol/kg/h of porcine pancreatic polypeptide (PP) were infused for 60 min. Secretin + CCK infusion was continued for 1 h after PP infusion was stopped. Each dose of PP was given on a separate day. Neither pancreatic flow nor bicarbonate output were affected whatever the dose of infused PP. On the contrary, protein concentration and output decreased with the lowest dose of PP (200 pmol/kg/h) and the diminution was more pronounced with the other doses. With 600 pmol/kg/h as well as with 800 and 1200 pmol/kg/h of PP, pancreatic protein output fell to about 20% of values obtained with secretin + CCK. Plasma levels of PP were below or similar to postprandial values for 200, 400 and 600 pmol/kg/h and they were significantly larger with 800 and 1200 pmol/kg/h. Protein concentration and output returned to values obtained with secretin + CCK infusion after cessation of PP infusion. In conclusion, porcine PP given in physiological doses to the pig decreases pancreatic protein output whereas pancreatic flow remains unaffected.     

Effects of cholecystokinin octapeptide on the pancreatic exocrine secretion in the pig

In conscious pigs, intravenous infusion of serial doses of cholecystokinin octapeptide (CCK8; 2.9-232.3 pmol.kg-1.min-1) upon a background of secretin resulted in a linear increase of plasma CCK-like immunoreactivity (CCK-LI) concentration and evoked a dose-related increase of pancreatic volume and bicarbonate and protein outputs. The threshold plasma CCK-LI concentration for significant pancreatic response was 103.8 +/- 10.2 pM using a CCK8 dose of 8.8 pmol.kg-1.min-1. The maximum pancreatic response was observed for a plasma CCK-LI level of 498.0 +/- 15.3 pM using 77.2 pmol CCK8.kg-1.min-1. In anesthetized pigs, the threshold plasma CCK-LI concentration for pancreatic response was 1500 pM (actual CCK8 dose of 60.3 pmol.kg-1.min-1). The physiological relevance of this finding was assessed by comparing the food-induced increase of pancreatic secretion with that of plasma CCK-LI. Food ingestion was followed by a sharp pancreatic response and by a progressive increase of plasma CCK-LI to a peak increment of about 15 pM. Gel chromatography of portal and peripheral plasma from fed animals revealed three major peaks in the volumes of CCK33/39 and CCK8, and in a volume intermediate between CCK33/39 and CCK8. An additional minor component eluted ahead of CCK33/39. CCK8, which is one of the CCK components released after food intake, appears to be a fairly weak pancreatic stimulant in pigs.     

Pyridoxine and atherosclerosis: role of pyridoxine in the metabolism of lipids and glycosaminoglycans in rats fed normal and high fat, high cholesterol diets containing 16% casein

The effect of administration of low and high doses of pyridoxine on the metabolism of lipids and glycosaminoglycans has been studied in rats fed normal and high fat, high cholesterol diets. Low doses of pyridoxine (0.005 mg/100 g body weight) caused increased concentrations, of cholesterol and triglycerides in the serum and aorta in animals fed normal and high fat, high cholesterol diets. Administration of high doses of pyridoxine (5.0 mg/100 g body weight) caused decrease in the concentration of these lipids in these tissues except in the case of the aorta in the animals fed a normal diet. Low doses of pyridoxine generally caused a decrease in the concentration of many glycosaminoglycan fractions in the aorta in rats fed normal and high fat, high cholesterol diets, whilst high doses caused an increase. The activity of glucosaminephosphate isomerase (glutamine-forming) and UDPglucose dehydrogenase, both key enzymes in the biosynthetic pathway of glycosaminoglycans, decreased in rats given low doses of pyridoxine and increased in rats given high doses. The activity of many enzymes concerned with degradation of glycosaminoglycans--hyaluronoglucosidase, beta-glucuronidase, beta-N-acetylglucosaminidase, aryl sulphatase, and cathepsin D--generally increased in rats fed low doses of the pyridoxine and decreased in those given high doses. The concentration of hepatic 3'-phosphoadenosine-5'-phosphosulphate, and the activity of the sulphate-activating system and of aryl sulphotransferase decreased when the dose of pyridoxine was low and increased when the dose was high.     

Effects of hypo- and hyper-thyroidism on liver composition, blood glucose, ketone bodies and insulin in the male rat

1. Thyroidectomized rats injected daily with 0, 0.1, 2 or 25mug of l-thyroxine/100g body wt. were compared with intact controls. In plasma, the protein-bound iodine was decreased in the rats given the 0 or 0.1mug doses and increased in those given the 25mug dose. 2. Blood glucose decreased in those given 2mug and was augmented in those given 25mug, and ketone bodies were the same in all the groups. 3. Plasma insulin was lowest in the rats given the 0 or 0.1mug doses and was highest in those given the 2 or 25mug doses of thyroxine. 4. After 48h starvation, the decrease in blood glucose and increase in ketone bodies observed in all the groups was greatest in the group not supplemented with thyroxine. 5. Plasma insulin concentrations remained at the value for fed animals in the rats given the 25mug dose of thyroxine but decreased in the other groups. 6. In fed animals, concentrations of hepatic DNA P, citrate, total fatty acids and acetyl-CoA were similar in all the groups, and glycogen was low only in the rats given the 25mug dose of thyroxine. 7. After 48h starvation, liver DNA P, total fatty acids and acetyl-CoA increased in all the groups, except in the rats given the 25mug dose, where both total fatty acids and acetyl-CoA remained at the value for fed animals. Liver citrate did not change in the groups given the 0 or 25mug doses of thyroxine, but decreased in the other groups. 8. The results are discussed in relation to the regulation of intermediary metabolism in hypo- and hyper-thyroidism.     

Effects of some gastrointestinal peptides on pancreatic growth in rats (preliminary results)

The purpose of this study was to estimate the effects of cholecystokinin (CCK), somatostatin (SS) pancreatic polypeptide (PP) and their interaction with each other, given them in single doses, on pancreatic secretion and pancreatic growth after long-term treatment in rats. The acute secretory effects of the above mentioned peptides were studied on conscious rats supplied with pancreatic, gastric and jugular vein cannulae. The pancreatic growth was characterized by measurements of pancreatic weight, desoxyribonucleic acid (DNA), protein, trypsin and amylase content after 5 days treatment. Amylase output was increased by caerulein alone, and given it in combination with somatostatin (SS), while its value decreased by SS alone. After 5 days treatment, the pancreatic weight, trypsin and amylase activity (hypertrophy) was increased by caerulein, and these values were not altered by S alone. In combinative administration of caerulein with somatostatin, the stimulatory effect by caerulein was decreased. PP given alone or in combination with caerulein decreased both the basal and stimulated amylase output. PP given for 5 days decreased pancreatic trypsin and amylase contents and counteracted the stimulatory effect by caerulein to these enzymes' contents. It has been concluded that: 1. caerulein stimulates both pancreatic enzyme secretion and pancreatic growth; 2. somatostatin inhibits the pancreatic secretion and caerulein induced pancreatic growth, but it does not affect the spontaneous growth of pancreas; 3. pancreatic polypeptide inhibits the pancreatic secretion and decreases pancreatic trypsin and amylase contents.     

Acute and subchronic influences of tetrahydrocannabinols on water and food intake, body weight, and temperature in rats.

Experiment 1. The acute effects of delta9-THC (1.25, 2.50, 5.00, and 10.00 mg/kg) and delta8-THC (1.25, 2.50, 5.00, and 10.00 mg/kg) was an approximately equipotent, dose related depression of water intake in water-deprived rats. Animals given hashish, inhaled as smoke, showed a depression of water consumption comparable to rats given the highest dose of either of the synthetic THCs. Water intake after chevril smoke was similar to that seen after vehicle injections. Experiment 2. A dose related depression of water-and-food intake, and reduction of body weight with a gradual recovery was found in rats, maintained on a Limited Time of drinking schedule (LT, 2 hr) and subchronically (21 days) treated with delta9-THC (1.25, 2.50, or 5.00 mg/kg). From the 22nd day all animals were given the vehicle only for 10 days. There were no indications of withdrawal effects due to the drug termination. Reinstating the drug after the 10 day drug free period suggested an increased sensitivity to THC as compared to the 21st injection. Experiment 3. In non-deprived rats delta9-THC caused similar effect as in Exp. 2, although to less extent. From both experiments it is concluded that there is an inhibition or even loss of body weight and that food intake seems more severely depressed than water intake. The temperature recordings suggest that the predominant consequence of lower, behaviorally, effective doses of THC on rectal temperature of rats is hyperthermia rather than hypothermia. Initially this effect was most pronounced for the lowest dose (1.25 mg/kg) but with repeated injections the two higher doses (2.50 and 5.00 mg/kg) showed hyperthermia to the same extent as the lowest dose. Hypothermia was seen after a high dose of delta8-THC (20.00 mg/kg) but after 3 daily injections this effect was gone.     

CCK-resistance in Zucker obese versus lean rats

Obese Zucker rats are less sensitive to the satiety effect of CCK than lean litter mates. The present studies further characterised this CCK resistance. Subcutaneous injection of the CCK agonist caerulein dose-dependently decreased food intake in Zucker obese and lean rats whereas the CCK-B agonist gastrin-17 did not. Caerulein at 4 μg/kg, which resulted in CCK plasma bioactivity slightly above postprandial levels, decreased food intake in lean rats but not in obese rats. The decrease in food intake was also more marked at higher caerulein doses (20–100 μg/kg) in lean versus obese rats. In lean animals the satiety effects of the “near physiological” 4 μg/kg caerulein dose was abolished after blockade of vagal afferents with capsaicin, whereas the effects of higher caerulein doses were not. CCK-stimulated amylase secretion from pancreatic acini and binding capacity of ¹²⁵I- labelled CCK-8 were decreased in obese versus lean rats. The CCK-A antagonist loxiglumide at 20 mg/kg, a dose which abolished the action of all caerulein doses on food intake, failed to alter the food intake either in obese or in lean rats when given without an agonist. The results suggest that the satiety effects of “near physiological” doses of caerulein in lean rats are mediated by vagal afferents whereas pharmacological doses act via non-vagal mechanisms. The differences in CCK's satiety effect between lean and obese rats may be due to differences in CCK-receptor binding and action at peripheral vagal sites. However, the failure of the CCK-A antagonist to increase food intake questions whether any of the effects of exogenous CCK are of physiological relevance.     

Cyclic nucleotides, calcium, bicarbonate, and protein secretion in canine pancreatic juice in response to cholecystokinin-pancreozymin.

The secretion of cyclic AMP, cyclic GMP, protein, calcium, and bicarbonate in the pancreatic juice of three nonanesthetized dogs with chronic gastric and duodenal Thomas cannulae has been studied. Intravenous infusions of increasing doses of cholecystokinin-pancreozymin (CCK) (1.5, 3, 6, 12, 24 Crick Harper-Raper (CHR) U kg-1 h-1) were administered together with a continuous submaximal dose of secretin (1 clinical unit (CU) kg-1 h-1). Doubling CCK doses every 45 min induced a parallel increase in the output of both cyclic nucleotides. Cyclic AMP output peaked at between 15 and 30 min for 3 and 6 U kg-1 h-1 of CCK and later for 12 and 24 U kg-1 h-1 of CCK whereas cyclic GMP output increased more constantly. Calcium output followed a pattern similar to that of cyclic GMP secretion. Flow rate and protein output attained their peaks at between 30 and 45 min. A strong linear correlation was found between the quantities of cyclic AMP, cyclic GMP, and the quantities of protein secreted in response to each CCK dose. This study demonstrates the presence of cyclic GMP in the canine pancreatic juice and the dose-dependent stimulation of the secretion of cyclic GMP and cyclic AMP by CCK in the presence of secretin.     

Central cardiovascular effects of mammalian neurohypophyseal peptides in conscious rats

To confirm and extend the results of previous studies which demonstrated central cardiovascular effects of vasopressin in anesthetized rats, we determined blood pressure and heart rate changes for 30 minutes after intracerebroventricular injections of arginine vasopressin, arginine vasotocin and oxytocin in conscious rats. As compared to sham injections, significantly greater increases in either systolic or diastolic blood pressure were noted over the 30 minutes which followed the injection of 0.15, 1.0 or 10.0 nM of either vasopressin or vasotocin. In animals given vasopressin, plasma levels of the peptide were determined. There was a substantial increase in plasma vasopressin only after the highest dose. Overall blood pressure responses to doses of oxytocin as high as 100 nM were not significantly different than sham injections. Heart rate following both vasopressin and vasotocin was increased at 0.15 nM, was initially decreased then increased at 1.0 nM and was substantially decreased after the 10.0 nM dose. There was a significant increase in heart rate at the 10.0 nM and 100 nM doses of oxytocin. Dose response curves for systolic blood pressure and heart rate 20 minutes after injection were similar for vasopressin and vasotocin. We conclude that arginine vasopressin has significant central pressor and tachycardic effects in conscious rats, and it is related, at least in part, to the tail structure of the peptide, which is shared with arginine vasotocin.     

Effects of pancreatic polypeptide on biliary flow and bile acid secretion stimulated by secretin and cholecystokinin in the conscious pig

Fourteen castrated male Large White pigs, weighing 42.5 +/- 1.0 kg, were fitted with biliary and duodenal fistulae for biliary secretion studies. Furthermore, catheters were placed in a carotid artery for blood sampling and in a jugular vein for peptide infusion. Bile was automatically restituted to the animals and continuously sampled for analysis on experimental days. Following an 8 day recovery period, infusion studies were performed after an overnight fast. After a 30 min basal period, sustained biliary flow and bile acid output were obtained and maintained throughout the assay with secretin (36 pmol/kg/h) and CCK-8 (600 pmol/kg/h) infusion. Then, 200, 400, 600, 800 or 1200 pmol/kg/h of porcine pancreatic polypeptide (PP) were infused for 60 min. Secretin plus CCK infusion was continued for 1 h after PP infusion was stopped. Each dose of PP was given on a separate day. Biliary flow was not affected by PP except for the dose of 400 pmol/kg/h. On the contrary, bile acid concentration and output decreased with the lowest dose of PP (200 pmol/kg/h). As soon as the first dose of PP was infused, bile acid concentration and output fell to about 60% of values obtained with secretin plus CCK. Plasma levels of PP were below or similar to postprandial values for 200, 400 and 600 pmol/kg/h and they were significantly larger with 800 and 1200 pmol/kg/h. Bile acid concentration and output did not return to values obtained with secretin plus CCK infusion after cessation of PP infusion. In conclusion, porcine PP given in physiological doses to the pig decreases bile acid output whereas biliary flow remains unaffected.     

CCK and PYY do not participate in the delayed inhibition of pancreatic secretion, after stimulation by duodenal oleic acid infusion.

The role played by CCK in the stimulation of pancreatic secretion by duodenal infusion of oleic acid in conscious rats was studied using a potent and specific CCK receptor antagonist. CR-1409 did not alter basal secretion, which does not require CCK. The three doses of CR-1409 that were used (2, 4 and 8 mg/kg/h) suppressed the protein response to duodenal infusion of oleic acid and significantly enhanced the delayed inhibition normally observed in control rats (-81%, -87% and -88% vs. -51% of basal in controls). CR-1409 dose-dependently reduced the volume of pancreatic secretion after duodenal infusion of oleic acid (0.40 +/- 0.02, 0.36 +/- 0.02, 0.34 +/- 0.03 vs. 0.48 +/- 0.04 ml/30 min for 2, 4, 8 mg/kg/h and controls, respectively) and revealed a delayed inhibition of volume and a slight reduction of bicarbonate secretion. CCK appears to be directly responsible for the protein and also water response to duodenal infusion of oleic acid, and to be indirectly involved in bicarbonate stimulation. PYY antiserum significantly augmented protein output after duodenal infusion of oleic acid (10.75 +/- 1.40, 14.10 +/- 1.60 vs. 8.60 +/- 1.20 mg/30 min, 1 microliter, 2 microliters and controls), but failed to modify the delayed inhibition: PYY modulates the response to duodenal infusion of oleic acid and is not involved in the delayed inhibition, which was shown to be also present for volume, but which is normally masked by the action of CCK.     

Cholecystokinin-dependent selective inhibitory effect on 'minute rhythm' in the ovine small intestine

Cholecystokinin (CCK) can exert multiple actions on intestinal motility but its effect on the small-intestinal 'minute rhythm' (MR) is virtually unknown. Therefore, the electrical activity from the abomasal antrum, duodenal bulb, duodenum, jejunum and ileum was continuously recorded in six sheep before, during and after slow intravenous administration, of three doses each, of cholecystokinin-octapeptide (CCK-OP) and cerulein. In four of these sheep, two additional electrodes and the strain gauge force transducer were also inserted in the duodenum. Chronic experiments were performed in the fasted and non-fasted animals and saline or CCK peptides were injected during phases 1, 2a or 2b of the duodenal migrating myoelectric complex (MMC). The administration of both CCK peptides in various doses evoked an inhibitory effect mostly in the duodenal bulb, except for the lowest dose of cerulein. The effects of 20 times greater doses of CCK-OP than that of cerulein were more pronounced. The introduction of both CCK peptides during phase 1 of the MMC produced no marked or significant response. In non-fasted animals, the effects of both hormonal peptides, given during phase 2b of the MMC, were often stronger than those given during phase 2a, while in fasted animals the effects of CCK peptides, administered in the course of phases 2a and 2b of the MMC, were similar. Both higher doses of CCK peptides increased the number of spike bursts within the given MR pattern in the duodenum and decreased the incidence of MR mostly in the duodenal bulb. The inhibitory effects of both CCK peptides on the bulbar MR exhibited a dose-response character, though the lowest dose often evoked the slight stimulatory response. It is concluded that CCK principally exerts an inhibitory effect upon the MR in the duodenal bulb and modifies the MR in the duodenum by increasing the spike burst number in a given MR pattern. Both these actions of CCK peptides seem to be physiological. There is a positive relationship between the intensity of the refractory period and the demonstrated effect of CCK in the duodenum.     

Effects of arginine vasotocin on levels of plasma gonadotropins and prolactin in ovariectomized conscious rats

Arginine vasotocin was injected into the third ventricle or intravenously in conscious, ovariectomized rats and its effect on gonadotropin and prolactin release evaluated. The peptide lowered plasma levels of both LH and prolactin in doses of 40 or 100 ng given intraventricularly. The higher dose was slightly more effective than the lower dose. Intravenous injection of a 1-microgram dose of vasotocin failed to alter plasma LH in the ovariectomized animals; however, a 5-micrograms dose induced a slight depression apparent at only 60 min following injection. Intravenous injection of 1 microgram produced a significant lowering of plasma prolactin, whereas a dramatic lowering followed the injection of the higher dose. Plasma FSH was unaffected in these experiments. Incubation of dispersed anterior pituitary cells from ovariectomized rats with various doses of vasotocin revealed no effect of the peptide on the release of FSH, LH, or prolactin. It also did not alter the response to LHRH, but it partially blocked the action of dopamine to inhibit prolactin release. The data indicate that quite low doses of arginine vasotocin act within the brain to inhibit LH and prolactin secretion in ovariectomized, conscious animals.     

Cardiovascular effects of cocaine in anesthetized and conscious rats

This study examined the cardiovascular and respiratory effects of cocaine and procaine in anesthetized and conscious rats. Intravenous cocaine (0.16-5 mg/Kg) elicited a rapid, dose dependent increase in mean arterial pressure of relatively short duration. In pentobarbital anesthetized (65 mg/Kg, i.p.) animals, the pressor phase was generally followed by a more prolonged depressor phase. These effects on arterial pressure were generally accompanied by a significant tachypnea and at larger doses (2.5 and 5 mg/Kg, i.v.), bradycardia. Procaine (0.31 and 1.25 mg/Kg, i.v.) produced similar cardiovascular and respiratory effects (depressor phase, tachypnea) in pentobarbital anesthetized animals. In conscious-restrained animals, both cocaine and procaine (1.25 mg/kg, i.v.) produced pressor responses. The subsequent depressor response was, however, absent in both cases. The cardiovascular effects of cocaine (0.25-1 mg/Kg, i.v.) in urethane anesthetized (1.25 g/Kg, i.p.) animals were essentially similar to those observed in conscious animals. Procaine (1mg/Kg) did not produce any significant cardiovascular effects in urethane anesthetized animals, but did elicit tachypnea. Reserpine pretreatment (10 mg/Kg, i.p.) did not significantly attenuate the pressor response in urethane anesthetized animals. Phentolamine pretreatment (3 mg/Kg, i.v.) did significantly antagonize the pressor effect in urethane anesthetized animals. These results suggest that: the depressor phase is likely due to a interaction between local anesthetic activity (cocaine and procaine) and barbiturate anesthesia, the cardiovascular effects of cocaine in conscious animals are more similar to those observed in urethane anesthetized rats than in pentobarbital anesthetized rats and the pressor effect in urethane anesthetized rats is apparently due to a reserpine resistant catecholaminergic mechanism.     

Dose-related involvement of CCK in bombesin-induced pancreatic growth.

We examined the role of CCK in bombesin-induced pancreatic growth in rats using the CCK receptor antagonist L-364,718. Rats (155 +/- 1 g, 8-10 per group) received subcutaneous injections every 8 h for 5 days with bombesin (0.6, 1.7 and 5 nmol/kg) or bombesin in combination with L-364,718 (1 mg/kg). After 5 days the pancreas was removed and pancreatic weight, protein content, DNA, amylase and chymotrypsin contents were determined. Bombesin produced a significant increase (48-475%) of pancreatic weight, tissue contents of protein, DNA, amylase and chymotrypsinogen (F = 82, P less than 0.001). When a large dose of bombesin (5 nmol/kg) was combined with L-364,718 a significant inhibition (up to 70%) of all tissue parameters was observed (P less than 0.001). L-364,718 did not affect the growth response to a small dose of bombesin (0.6 nmol/kg). Plasma CCK levels 15 min after a single injection of bombesin (0.6, 1.7 and 5 nmol/kg) were significantly increased in response to the 5 nmol/kg dose (2.0 +/- 0.7 to 3.4 +/- 0.8 pM, F = 6.9, P less than 0.01). No increases of CCK plasma levels were found in response to the 0.6 and 1.7 nmol/kg doses of bombesin, corresponding to the lack of effects of L-364,718 on growth parameters at these doses. Measuring the time-course of CCK plasma levels after a single injection of 5 nmol/kg bombesin revealed an increase from basal values of 1.4 +/- 0.3 pM to maximal levels of 3.5 +/- 0.5 pM after 15 min (F = 7.1, P less than 0.001). Values returned to basal after 60 min. These results suggest that low doses of bombesin act directly at the acinar cell or through release of non-CCK growth factors whereas high doses of bombesin act in part through CCK release.