Brain angiotensinergic mediation of enhanced water consumption in lactating rats

The mechanism by which lactating rats increase fluid consumption to meet the demands of milk production is unknown. Because ANG II is the most potent dipsogenic stimulus known, this study examined whether angiotensinergic signaling plays a role in enhanced drinking in lactating rats. ANG II administered intracerebroventricularly caused a significantly greater dipsogenic response in lactating rats than in control rats, suggesting that dipsogenic responsivity to ANG II is enhanced in the brains of lactating rats. The angiotensin type 1 (AT1) ANG II receptor subtype antagonist SKF-108566, also given intracerebroventricularly, caused a significant reduction in water consumption in lactating rats, whereas it did not significantly affect water intake in control rats. In contrast, stimulation of drinking by the muscarinic agonist carbachol, also administered intracerebroventricularly, did not differ between lactating and control rats. Inhibition of drinking by the muscarinic antagonist atropine also did not differ significantly between lactating and control rats. These results suggest that the increased drinking in lactating rats involves an increased responsivity to ANG II in neurons that mediate dipsogenesis, as well as an enhancement in the amount of angiotensinergic input to these ANG II-responsive neurons.     

Investigation of the mechanisms involved in the central effects of glucagon-like peptide-1 on ethanol-induced gastric mucosal lesions

The aim of this study was to investigate the effects of intracerebroventricularly injected glucagon-like peptide-1 (GLP-1) on ethanol-induced gastric mucosal damage and to elucidate the mechanisms involved. Absolute ethanol was administered through an orogastric cannula 5 min before GLP-1 (1 microg/10 microl) injection. One hour later, the rats were decapitated, their stomachs were removed and scored for mucosal damage. GLP-1 inhibited the ethanol-induced gastric mucosal damage by 92%. Centrally injected atropine sulphate, a muscarinic receptor antagonist (5 microg/10 microl), prevented the gastroprotective effect of GLP-1, while mecamylamine, a nicotinic receptor antagonist (25 microg/10 microl), was ineffective. Peripherally injected atropine methyl nitrate (1 mg/kg) did not change the effect of GLP-1, but mecamylamine (5 mg/kg) blocked it. Cysteamine, a somatostatin depletor (280 mg/kg, s.c.), did not affect the protective activity of GLP-1, while inhibition of nitric oxide (NO) synthesis by L-NAME (3 mg/kg, i.v.) significantly abolished the protective effect of GLP-1 on ethanol-induced gastric mucosal lesions. We conclude that central muscarinic and peripheral nicotinic cholinergic receptors and NO, but not somatostatin, contribute to the protective effect of intracerebroventricularly injected GLP-1 on ethanol-induced gastric mucosal damage.     

Central angiotensin receptor blockade impairs thermolytic and dipsogenic responses to heat exposure in rats

The effect of central angiotensin AT(1) receptor blockade on thermoregulation and water intake after heat exposure was investigated. Rats were placed in a chamber heated to 39 +/- 1 degrees C for 60 min and then returned to their normal cage (at 22 degrees C), and water intake was measured for 120 min. Artificial cerebrospinal fluid (5 microl) was injected intracerebroventricularly 60 min before heat exposure in five control rats. Colonic temperature increased from 37.22 +/- 0.21 to 40.68 +/- 0.31 degrees C after 60 min. In six rats injected intracerebroventricularly with 10 microg of the AT(1) antagonist losartan, colonic temperature increased from 37.41 +/- 0.27 to 41.72 +/- 0.28 degrees C after 60 min. This increase was significantly greater than controls (P < 0.03). Losartan-treated rats drank 1.1 +/- 0.4 ml of water compared with 5.9 +/- 0.77 ml (P < 0.002) drank by control animals, despite a similar body weight loss in the two groups. Central losartan did not inhibit the drinking response to intracerebroventricular carbachol in heated rats, suggesting that losartan treatment did not nonspecifically depress behavior. We conclude that central angiotensinergic mechanisms have a role in both thermoregulatory cooling in response to heat exposure and also the ensuing water intake.     

A central link between angiotensinergic and cholinergic systems; role of vasopressin

Participation of central cholinergic system in the effects of intracerebroventricular (i.c.v.) injection of angiotensin II (Ang II) on blood pressure and heart rate was studied in conscious, freely moving rats. Ang II dose-dependently increased blood pressure and decreased heart rate. Both atropine and mecamylamine (i.c.v.) pretreatments prevented the cardiovascular effects of Ang II. Pretreatment with a vasopressin V1 antagonist also prevented the cardiovascular responses to Ang II. Our data suggest that the central pressor effect of Ang II is mediated in part by central acetylcholine via both muscarinic and nicotinic receptors, and vasopressin participates in this effect through V1 receptors.     

Peripheral mechanisms involved in the pressor and bradycardic effects of centrally administered arachidonic acid

In the current study, we aimed to determine the cardiovascular effects of arachidonic acid and peripheral mechanisms mediated these effects in normotensive conscious rats. Studies were performed in male Sprague Dawley rats. Arachidonic acid was injected intracerebroventricularly (i.c.v.) at the doses of 75, 150 or 300 microg and it caused dose- and time-dependent increase in mean arterial pressure and decrease in heart rate in normal conditions. Maximal effects were observed 10 min after 150 and 300 microg dose of arachidonic acid and lasted within 30 min. In order to evaluate the role of main peripheral hormonal mechanisms in those cardiovascular effects, plasma adrenaline, noradrenaline, vasopressin levels and renin activity were measured after arachidonic acid (150 microg; i.c.v.) injection. Centrally injected arachidonic acid increased plasma levels of all these hormones and renin activity. Intravenous pretreatments with prazosin (0.5 mg/kg), an alpha1 adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl1, O-Me-Tyr2-Arg8]-vasopressin (10 microg/kg), a vasopressin V1 receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, partially blocked the pressor response to arachidonic acid (150 microg; i.c.v.) while combined administration of these three antagonists completely abolished the effect. Moreover, both individual and combined antagonist pretreatments fully blocked the bradycardic effect of arachidonic acid. In conclusion, our findings show that centrally administered arachidonic acid increases mean arterial pressure and decreases heart rate in normotensive conscious rats and the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity appear to mediate the cardiovascular effects of the drug.     

Effects of intracerebroventricularly injected glucagon-like peptide-1 on cardiovascular parameters; role of central cholinergic system and vasopressin

We aimed to investigate the effects of intracerebroventricularly (i.c.v.) injected glucagon-like peptide-1 (GLP-1) on blood pressure and heart rate, and whether central cholinergic system and vasopressinergic system play roles in these effects. Male Wistar albino rats were used throughout the experiments. Blood pressures and heart rates were observed before and for 30 min following drug injections. i.c.v. GLP-1 (100, 500 and 1000 ng/10 microl) caused a dose-dependent increase in both blood pressure and heart rate. Nicotinic receptor antagonist mecamylamine (25 microg/10 microl, i.c.v.) and muscarinic receptor antagonist atropine (5 microg/10 microl, i.c.v.) prevented the stimulating effect of GLP-1 on blood pressure. The effect of GLP-1 on heart rate was blocked only by mecamylamine. The V1 receptor antagonist of vasopressin (B-mercapto B, B-cyclopentamethylenepropionyl, O-Me-Tyr,Arg)-vasopressin (10 microg/kg), that was applied intraarterially, only prevented the effect of GLP-1 on blood pressure, but did not show any effect on heart rate. Our data indicate that i.c.v. GLP-1 increases blood pressure and heart rate, and stimulation of central nicotinic and partially muscarinic receptors and vasopressinergic system play a role in the effects of i.c.v. GLP-1 on blood pressure. The effect of GLP-1 on heart rate may be partially due to stimulation of central nicotinic receptors.     

Neuronostatin acts in brain to biphasically increase mean arterial pressure through sympatho-activation followed by vasopressin secretion: the role of melanocortin receptors

Neuronostatin is a recently described neuropeptide that is derived from the somatostatin preprohormone. We have shown previously that neuronostatin led to a biphasic, dose-related increase in mean arterial pressure when injected into the lateral cerebroventricle of adult, male rats. Because neuronostatin depolarized both magnocellular and parvocellular, paraventricular nucleus neurons in hypothalamic slice preparations, we hypothesized that neuronostatin elevated mean arterial pressure first by stimulating sympathetic nervous system activity followed by the release of a pressor hormone, specifically vasopressin. We found that the first phase of neuronostatin-induced increase in mean arterial pressure was reversed by pretreatment with phentolamine, indicating that phase 1 was, indeed, due to an increase in sympathetic activity. We also found that centrally injected neuronostatin led to a dose-related increase in vasopressin secretion in a time course consistent with the peak of the second phase. Furthermore, the second phase of arterial pressure elevation was reversed by pretreatment with a vasopressin 1 receptor antagonist, indicating that phase 2 was likely due to an increase in vasopressin secretion. We previously have shown that the anorexigenic and antidipsogenic effects of neuronostatin were reversed by pretreatment with the melanocortin 3/4 receptor antagonist, SHU9119, so we evaluated the ability of SHU9119 to reverse the effects of neuronostatin on MAP and vasopressin secretion. We found that SHU9119 abrogated the second phase of neuronostatin-induced increase in MAP and neuronostatin-induced vasopressin secretion, indicating that neuronostatin acts through the central melanocortin system to increase vasopressin release, ultimately leading to an elevation in MAP.     

Role of intracerebroventricular vasopressin in the development of stress-induced gastric lesions in rats

We investigated whether arginine vasopressin (AVP) has a central influence on the development of gastric mucosal lesions evoked by restraint-cold stress in rats. AVP and vasopressin V1 receptor antagonist were injected intracerebroventricularly (i.c.v.) and the rats were exposed to restraint-cold stress for five hours. After decapitation the stomachs were examined for gastric mucosal lesions which were evaluated according to an ulcer score. Three different doses of AVP and V1 receptor antagonist were administered in order to investigate the effects of exogenous and endogenous AVP on stress-induced gastric mucosal lesions. The intensity of gastric mucosal lesions was reduced when exogenous AVP was injected intracerebroventricularly. On the other hand, vasopressin V1 receptor antagonist, which was administered by the same route, augmented gastric mucosal lesions. Our findings indicate that AVP, injected centrally, plays a role in preventing the formation of gastric mucosal lesions induced by stress via a central V1 receptor.     

The brain renin-angiotensin system: location and physiological roles

Angiotensinogen, the precursor molecule for angiotensins I, II and III, and the enzymes renin, angiotensin-converting enzyme (ACE), and aminopeptidases A and N may all be synthesised within the brain. Angiotensin (Ang) AT(1), AT(2) and AT(4) receptors are also plentiful in the brain. AT(1) receptors are found in several brain regions, such as the hypothalamic paraventricular and supraoptic nuclei, the lamina terminalis, lateral parabrachial nucleus, ventrolateral medulla and nucleus of the solitary tract (NTS), which are known to have roles in the regulation of the cardiovascular system and/or body fluid and electrolyte balance. Immunohistochemical and neuropharmacological studies suggest that angiotensinergic neural pathways utilise Ang II and/or Ang III as a neurotransmitter or neuromodulator in the aforementioned brain regions. Angiotensinogen is synthesised predominantly in astrocytes, but the processes by which Ang II is generated or incorporated in neurons for utilisation as a neurotransmitter is unknown. Centrally administered AT(1) receptor antagonists or angiotensinogen antisense oligonucleotides inhibit sympathetic activity and reduce arterial blood pressure in certain physiological or pathophysiological conditions, as well as disrupting water drinking and sodium appetite, vasopressin secretion, sodium excretion, renin release and thermoregulation. The AT(4) receptor is identical to insulin-regulated aminopeptidase (IRAP) and plays a role in memory mechanisms. In conclusion, angiotensinergic neural pathways and angiotensin peptides are important in neural function and may have important homeostatic roles, particularly related to cardiovascular function, osmoregulation and thermoregulation.     

The effect of linear somatostatin on the active avoidance behaviour and open-field activity on haloperidol, phenoxybenzamine and atropine pretreated rats

Somatostatin administered intracerebroventricularly inhibited the extinction of active avoidance behaviour. The dopamine receptor blocking agent haloperidol, the alpha 1-receptor blocker phenoxybenzamine and the muscarinic anticholinergic agent atropine inhibited the behavioural effect of the peptide. Furthermore, somatostatin increased the locomotor activity of the animals. Neither of these drugs influenced the effect of the peptide exerted on locomotor activity. The peptide was ineffective on other parameters of the open-field test while phenoxybenzamine decreased the defecation rate of the animals and this effect was not influenced by somatostatin. The results suggest that the catecholaminergic and the cholinergic system play an important role in the inhibition of extinction produced by somatostatin but these mechanisms to not have a role in the locomotor activity induced by the peptide.     

Reciprocal paracrine pathways link atrial natriuretic peptide and somatostatin secretion in the antrum of the stomach

Atrial natriuretic peptide (ANP) as well as its receptor, NPR-A, have been identified in gastric antral mucosa, suggesting that ANP may act in a paracrine fashion to regulate gastric secretion. In the present study, we have superfused antral mucosal segments obtained from rat stomach to examine the paracrine pathways linking ANP and somatostatin secretion in this region.ANP (0.1 pM to 0.1 microM) caused a concentration-dependent increase in somatostatin secretion (EC(50), 0.3 nM). The somatostatin response to ANP was unaffected by the axonal blocker tetrodotoxin but abolished by addition of the selective NPR-A antagonist, anantin. Anantin alone inhibited somatostatin secretion by 18+/-3% (P<0.005), implying that endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion. Somatostatin (1 pM to 1 microM) caused a concentration-dependent decrease in ANP secretion (EC(50), 0.7 nM) that was abolished by addition of the somatostatin subtype 2 receptor (sst2) antagonist, PRL2903. Neutralization of ambient somatostatin with somatostatin antibody (final dilution 1:200) increased basal ANP secretion by 70+/-8% (P<001), implying that endogenous somatostatin inhibits ANP secretion. We conclude that antral ANP and somatostatin secretion are linked by paracrine feedback pathways: endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion, and endogenous somatostatin, acting via the sst2 receptor, inhibits ANP secretion.     

Urethane-induced somatostatin mediated inhibition of gastric acid: reversal by the somatostatin 2 receptor antagonist, PRL-2903.

Urethane increases the release of somatostatin (SRIF) which inhibits gastric acid secretion. The SRIF monoclonal antibody, CURE.S6 and the novel sst2 antagonist, PRL-2903 injected intravenously at maximal effective doses increased gastric acid secretion by 2 and 10 fold respectively from basal values within 30 min in urethane-anesthetized rats. Plasma gastrin levels were elevated 2.5 fold within 15 min by PRL-2903 (1.3 micromol/kg, i.v.). These data indicate that the low gastrin and acid secretion levels induced by urethane result from endogenous SRIF acting on sst2 and that PRL-2903 is a valuable SRIF antagonist to assess sst2 mediated events.     

Vasopressin pressor antagonist injected centrally reverses behavioral effects of peripheral injection of vasopressin, but only at doses that reverse increase in blood pressure

Previous work in rats (Ader, R. and De Wied, D., Psychon. Sci., 29 (1972) 46-48) has established that subcutaneously (s.c.) injected arginine vasopressin (AVP) prolongs extinction of active avoidance and that this effect could be prevented by pretreatment with the vasopressin antagonist analog [1-deaminopenicillamine, 2-(O-methyl)tyrosine]-beta-arginine vasopressin (dPtyr(Me)AVP). The purpose of the present study was to determine if peripherally administered AVP acts via a peripheral blood pressure effect or by a direct action in the central nervous system. We therefore tested the effects of the antagonist injected intracerebroventricularly (i.c.v.) on the prolongation of active avoidance and on blood pressure effects of s.c. injected AVP. The antagonist (i.c.v.) blocked the behavioral effects of systemically injected AVP only at dose sufficient to block the peripherally mediated pressor response of systemically administered AVP. The results show that peripherally injected AVP acts on peripheral systems and support our hypothesis that the peripheral visceral action of AVP contributed significantly to its behavioral action.     

Modulation of acetylcholine-induced secretion of gastric bombesin-like immunoreactivity by cholinergic and histamine H2-receptors, somatostatin and intragastric pH

Recently we have shown the release of bombesin-like immunoreactivity (BLI) from the isolated perfused rat stomach. In these experiments we have shown that BLI secretion is stimulated by acetylcholine. Gastric inhibitory peptide (GIP) exerts an inhibitory effect which is dependent on the intraluminal pH. The present study was designed to examine further the exact cholinergic mechanisms and to study the interaction between cholinergic and histaminergic mechanisms as well as the effect of the intraluminal pH. Acetylcholine elicited a dose-dependent increase in BLI and gastrin secretion (10(-6) M and 2 X 10(-6)M), whereas somatostatin release was suppressed at luminal pH 7. Blockade of muscarinic cholinergic receptors by atropine (10(-5)M) and nicotinic cholinergic receptors by hexamethonium (10(-5) M) abolished the effect of acetylcholine on all three peptides. Reduction of the intraluminal pH to 2 also abolished acetylcholine-induced stimulation of BLI and gastrin secretion and the inhibition of somatostatin secretion. Changes of intraluminal pH per se had no effect on the secretion of either peptide. Somatostatin (10(-7) M) reduced both BLI and gastrin secretion during stimulation with acetylcholine. The addition of the H2-receptor antagonist cimetidine (10(-5) M) abolished the effect of both doses of acetylcholine on BLI and somatostatin secretion and also the effect of the lower dose of acetylcholine (10(-6) M) on gastrin secretion during luminal pH 7. At luminal pH 2 cimetidine did not alter BLI and somatostatin secretion in response to acetylcholine, however, gastrin release was augmented in the presence of cimetidine. These data demonstrate that the effect of acetylcholine on BLI, gastrin, and somatostatin secretion is mediated by muscarinic and nicotinic cholinergic receptors and also by histamine H2-receptors. Somatostatin inhibits cholinergically induced BLI secretion. The cholinergic effects on BLI, somatostatin and gastrin secretion are abolished during an acidic intragastric pH. In this isolated perfused rat stomach model the inhibitory effect of intraluminal acid on gastrin secretion is, at least in part, mediated by H2-receptors. This suggests that the secretion of bombesin, a potential peptidergic neurotransmitter is modulated by neural, endocrine and local tissue factors and also by alterations of intragastric pH.     

Central administration of angiotensin II receptor antagonists and arterial pressure regulation: a note of caution.

The blunting of arterial pressure increases to a variety of pressor agents or the lowering of arterial pressure in some models of hypertension following intracerebroventricular administration of an angiotensin II (AII) antagonist, has been interpreted as prima facie evidence for the involvement of the central AII system in these situations. Central administration of vasopressin or carbachol (a cholinergic agonist) produces pressor effects which have been reported to be due to an increase in the activity of the sympathetic nervous system. We now report that central administration of AII antagonists [either (Sar-1, Ile-8) AII or (Sar-1, Ala-8) AII] in rats prevents the majority (greater than 70%) of the pressor effects of intraventricular vasopressin or carbachol. These results can be interpreted in two ways. The first is that all of these pressor agents use a central angiotensinergic mechanism(s) to increase sympathetic nervous system activity. An alternative hypothesis is that centrally administered AII antagonists non-specifically inhibit sympathetic nervous system function.     

Microinjection of exogenous somatostatin in the dorsal vagal complex inhibits pancreatic secretion via somatostatin receptor-2 in rats

Previous studies have suggested that somatostatin inhibits pancreatic secretion at a central vagal site, and the dorsal vagal complex (DVC) is involved in central feedback inhibition of the exocrine pancreas. The aim of this study was to investigate the effect of exogenous somatostatin in the DVC on pancreatic secretion and the somatostatin receptor subtype(s) responsible for the effect. The effects of somatostatin microinjected into the DVC on pancreatic secretion stimulated by cholecystokinin octapeptide (CCK-8) or 2-deoxy-d-glucose (2-DG) were examined in anesthetized rats. To investigate the somatostatin inhibitory action site, a somatostatin receptor antagonist [SRA; cyclo(7-aminoheptanoyl-Phe-d-Trp-Lys-Thr)] was microinjected into the DVC before intravenous infusion of somatostatin and CCK-8/2-DG. The effects of injection of a somatostatin receptor-2 agonist (seglitide) and combined injection of somatostatin and a somatostatin receptor-2 antagonist (CYN 154806) in the DVC on the pancreatic secretion were also investigated. Somatostatin injected into the DVC significantly inhibited pancreatic secretion evoked by CCK-8 or 2-DG in a dose-dependent manner. SRA injected into the DVC completely reversed the inhibitory effect of intravenous administration of somatostatin. Seglitide injected into the DVC also inhibited CCK-8/2-DG-induced pancreatic protein secretion. However, combined injection of somatostatin and CYN 154806 did not affect the CCK-8/2-DG-induced pancreatic secretion. Somatostatin in the DVC inhibits pancreatic secretion via somatostatin receptor-2, and the DVC is the action site of somatostatin for its inhibitory effect.     

Centrally administered vasopressin antagonizes pentobarbital-induced narcosis and depression of hippocampal cholinergic activity

Intracerebroventricular (ICV) microinjection of arginine vasopressin (AVP) to pentobarbital-anesthetized rats produced shortening of the duration of narcosis. This analeptic effect was blocked by atropine, indicating the central cholinergic nature of the response. AVP also increased hippocampal sodium-dependent high affinity choline uptake activity that had been depressed by the barbiturate. The AVP analeptic effect was blocked by pretreatment with a V-1 (vasopressor), but not a V-2 (antidiuretic), vasopressin receptor antagonist. These results suggest that ICV AVP produces its analeptic effect by interacting with central V-1 receptors to activate a hippocampal cholinergic arousal system. The cholinergic arousal effect may be a factor in the memory enhancing property of AVP.     

Serotonergic mechanisms of the lateral parabrachial nucleus and cholinergic-induced sodium appetite

Central cholinergic mechanisms are suggested to participate in osmoreceptor-induced water intake. Therefore, central injections of the cholinergic agonist carbachol usually produce water intake (i.e., thirst) and are ineffective in inducing the intake of hypertonic saline solutions (i.e., the operational definition of sodium appetite). Recent studies have indicated that bilateral injections of the serotonin receptor antagonist methysergide into the lateral parabrachial nucleus (LPBN) markedly increases salt intake in models involving the activation of the renin-angiotensin system or mineralocorticoid hormones. The present studies investigated whether sodium appetite could be induced by central cholinergic activation with carbachol (an experimental condition where only water is typically ingested) after the blockade of LPBN serotonergic mechanisms with methysergide treatment in rats. When administered intracerebroventricularly in combination with injections of vehicle into both LPBN, carbachol (4 nmol) caused water drinking but insignificant intake of hypertonic saline. In contrast, after bilateral LPBN injections of methysergide (4 microg), intracerebroventricular carbachol induced the intake of 0.3 M NaCl. Water intake stimulated by intracerebroventricular carbachol was not changed by LPBN methysergide injections. The results indicate that central cholinergic activation can induce marked intake of hypertonic NaCl if the inhibitory serotonergic mechanisms of the LPBN are attenuated.     

A multi-tyrosinated sst1/2 receptor preferring somatostatin agonist inhibits reflex and immune-mediated secretion in the guinea pig colon

Somatostatin and its analogs such as WOC 3B were compared for their ability to alter the release of 5-hydroxytryptamine (5-HT) and prostaglandins and to affect chloride secretory capacity, determined by activity of neural reflexes or by the influence of immune mediators and other secretagogues. In guinea pig colon set up in flux chambers, the multi-tyrosinated sst1/sst2 receptor preferring somatostatin agonist, WOC 3B, inhibited stroking-evoked 5-HT release without affecting basal release. WOC 3B had no effect on stroking-induced or basal prostaglandin E2 release (PGE2). Neither 5-HT nor PGE2 release was dependent on neural input. Tetrodotoxin induced a decrease in basal short circuit current (Isc) indicative of a decrease in chloride secretion. The decrease in basal Isc during neural blockade was highly correlated with the decrease in basal Isc when WOC 3B was used. In piroxicam- and atropine-treated tissues, to eliminate prostaglandins and cholinergic muscarinic input to crypts, WOC 3B further reduced the piroxicam-resistant and not the atropine resistant Isc during brush stroking the mucosa. Somatostatin and WOC 3B reduced the stroking-evoked Isc with similar half maximum concentrations of 1-2 nM. WOC 3B reduced by more than 50% dimaprit-evoked cyclical Isc. The rank order of potencies in inhibiting dimaprit-evoked Isc was: Somatostatin-14=WOC 3B>CH275=DC-32-92>DC-23-48> >DC-32-87=DC-32-97. Low nanomolar concentrations of WOC 3B primarily inhibited the neural effects of carbachol and forskolin on Isc without altering their epithelial effects. Equi-molar concentrations (4 nM) of CH275, a somatostatin sst1 receptor agonist, and the somatostatin sst2 receptor agonist, [Tyr(3)]-octreotide, inhibited dimaprit-evoked Isc by 25% and 26%, and their effects were additive. The results suggest that WOC 3B, a somatostatin analogue containing three tyrosine residues, has anti-secretory effects due to activation of somatostatin sst1 and sst2 receptors on enteric neurons.     

Involvement of different mechanisms in the stimulatory effects of cholecystokinin octapeptide on gastrointestinal and colonic motility in dogs

The effects of an intravenous infusion of cholecystokinin octapeptide (CCK-8, 1 microgram.kg-1.h-1) were investigated in conscious fasted dogs chronically fitted with strain-gauge transducers on the antrum, the jejunum, and the colon. Attempts to antagonize the increase of motility appearing at the three levels during CCK infusion were made using different blockers to elucidate the mechanisms involved. Asperlicin (a specific CCK antagonist) blocked the effects of CCK-8 at the three levels, while atropine and somatostatin were only effective in the jejunum and colon. Methyl-levallorphan (a mu-opiate antagonist that poorly crosses the blood-brain barrier) antagonized the CCK-induced colonic stimulation when intracerebroventricularly administered. Serotonin, histamine, substance P, and K-antagonists as well as a benzodiazepine did not modify the CCK-8 induced stimulation. It was concluded that the stimulatory effect of CCK-8 resulted from (a) a direct stimulation of the smooth muscle cells at gastric level, (b) a cholinergic activation of the jejunum and the colon, and (c) the involvement of a mu-opioid central component in the colonic response only.