The inhibition of cholera toxin-induced 5-HT release by the 5-HT(3) receptor antagonist, granisetron, in the rat

1. The secretagogue 5-hydroxytryptamine (5-HT) is implicated in the pathophysiology of cholera. 5-HT released from enterochromaffin cells after cholera toxin exposure is thought to activate non-neuronally (5-HT(2) dependent) and neuronally (5-HT(3) dependent) mediated water and electrolyte secretion. CT-secretion can be reduced by preventing the release of 5-HT. Enterochromaffin cells possess numerous receptors that, under basal conditions, modulate 5-HT release. 2. These include basolateral 5-HT(3) receptors, the activation of which is known to enhance 5-HT release. 3. Until now, 5-HT(3) receptor antagonists (e.g. granisetron) have been thought to inhibit cholera toxin-induced fluid secretion by blockading 5-HT(3) receptors on secretory enteric neurones. Instead we postulated that they act by inhibiting cholera toxin-induced enterochromaffin cell degranulation. 4. Isolated intestinal segments in anaesthetized male Wistar rats, pre-treated with granisetron 75 microg kg(-1), lidoocaine 6 mg kg(-1) or saline, were instilled with a supramaximal dose of cholera toxin or saline. Net fluid movement was determined by small intestinal perfusion or gravimetry and small intestinal and luminal fluid 5-HT levels were determined by HPLC with fluorimetric detection. 5. Intraluminal 5-HT release was proportional to the reduction in tissue 5-HT levels and to the onset of water and electrolyte secretion, suggesting that luminal 5-HT levels reflect enterochromaffin cell activity. 6. Both lidocaine and granisetron inhibited fluid secretion. However, granisetron alone, and proportionately, reduced 5-HT release. 7. The simultaneous inhibition of 5-HT release and fluid secretion by granisetron suggests that 5-HT release from enterochromaffin cells is potentiated by endogenous 5-HT(3) receptors. The accentuated 5-HT release promotes cholera toxin-induced fluid secretion.     

Role of mast cells and pro-inflammatory mediators on the intestinal secretion induced by cholera toxin.

Recent data suggest that diarrhea caused by Vibrio cholerae involves a pro-inflammatory mediators release, such as cytokines, prostaglandin and nitric oxide. The aim of this study was to investigate the role of mast cells and their mediators in the intestinal secretion induced by cholera toxin. We examined the dose responses, time course and role of mast cells and pro-inflammatory mediators in cholera toxin intestinal secretory response, in vivo. Cholera toxin caused a dose-dependent secretion, in ligated small intestine loops, at 18 h. Rats treated with 48/80 compound or ketotifen had a significant decrease in the intestinal secretory response. Cholera toxin secretion was significantly reduced by an unspecific histamine/serotonin receptor antagonist, histamine receptor antagonist, phospholipase A2 and cyclooxygenase inhibitors, platelet-activating factor (PAF) receptor antagonists and TNF-alpha synthesis blockers. On the other hand, pretreatment with a specific serotonin receptor antagonist and lipoxygenase inhibitors failed to block this effect. Analysis of the intestinal fluid from rats injected with cholera toxin, revealed that cholera toxin induces the release of IL-1beta and TNF-alpha into fluid. The data suggest that, at least in part, mast cells are involved in cholera toxin-induced secretion, as well as point to the importance of histamine, prostaglandins, PAF, IL-1beta and TNF-alpha in this process.     

5-HT receptor antagonists and heat-stable Escherichia coli enterotoxin-induced effects in the rat.

The effect of heat-stable E. coli enterotoxin on intestinal fluid secretion is commonly considered to be mediated by stimulation of mucosal cyclic guanosine monophosphate (cGMP). It was demonstrated recently that 5-hydroxytryptamine (5-HT) acts as an important mediator in cholera toxin-induced fluid secretion. To elucidate the possible involvement of 5-HT in the secretory response to heat-stable E. coli enterotoxin, in vivo experiments were performed in the rat jejunum. The inhibitory effects of the 5-HT2 receptor antagonist ketanserin, the 5-HT3 receptor antagonist tropisetron and indomethacin were studied in heat-stable E. coli enterotoxin-induced fluid secretion. Tropisetron and ketanserin (100 micrograms/kg each) alone only partially reduced the secretory effect of the toxin. However, in combination, the two blockers (100 plus 100 micrograms/kg) significantly reduced and at 200 plus 200 micrograms/kg totally abolished heat-stable E. coli enterotoxin-induced secretion without influencing the enterotoxin-induced increase in cGMP. Pretreatment with indomethacin (10 mg/kg) reduced the secretory response to the enterotoxin by about 50%. These results support the concept that 5-HT is an important mediator in intestinal fluid secretion induced by heat-stable E. coli enterotoxin. The enterotoxin may use 5-HT to stimulate prostaglandin formation via 5-HT2 receptors and to activate neuronal structures via 5-HT3 receptors.     

Inhibition of cholera toxin-induced intestinal secretion by the 5-HT3 receptor antagonist ICS 205–930

Summary The secretory effect of cholera toxin on the gut has been ascribed to the activation of submucosal 5-hydroxytryptamine receptors by 5-hydroxytryptamine released from the enterochromaffin cells. The hypothesis that neuronally located 5-HT₃ receptors are involved in cholera toxin-induced diarrhoea has now been tested. Intestinal secretion was stimulated in mice by oral administration of pure cholera toxin and the effects of ICS 205-930, a potent and selective antagonist at 5-HT₃ receptors, and of ketanserin, a compound that blocks 5-HT₂ receptors, were investigated.Oral administration of cholera toxin resulted in a significant accumulation of fluid in the intestine. Pretreatment of the animals with ICS 205–930 partly prevented this effect and a maximal reduction of about 50% was achieved with doses of 0.3 mg/kg i. p. and higher. Ketanserin had only minimal effects up to a high dose of 1 mg/kg i. p. when a 20% reduction of fluid accumulation was seen. The data support the view that activation of 5-HT3 receptors plays a major role in the secretory effect of cholera toxin in the gut.     

Role of serotonin in the pathophysiology of the irritable bowel syndrome

The irritable bowel syndrome (IBS) is a complex disorder that is associated with altered gastrointestinal motility, secretion, and sensation. Serotonin (5-HT) is an important neurotransmitter and paracrine signalling molecule in the gastrointestinal tract. 5-HT release from enterochromaffin (EC) cells initiates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. The enteric nervous system (ENS) comprises a semiautonomous effector system that is connected to the central autonomic network. Parasympathetic and sympathetic nerves modulate the ENS via afferent and efferent communications. Ongoing, bidirectional brain-gut interactions involving 5-HT pathways occur that significantly influence the effector systems. Altered 5-HT signalling may lead to both intestinal and extraintestinal symptoms in IBS. 5-HT directly and indirectly affects intestinal motor and secretory function and abnormalities may lead to either constipation or diarrhea. 5-HT modulates sensation and perception of visceral stimulation at peripheral and central sites. Therapeutic agents targeting altered 5-HT signalling may provide new, effective treatments for patients with IBS.     

Effect of the 5-hydroxytryptamine3 (5-HT3)-receptor antagonist KB-R6933 on experimental diarrhea models.

The effects of a 5-hydroxytryptamine3 (5-HT3)-receptor antagonist KB-R6933 (6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-benzimidazole dimaleate) on experimental diarrhea and on intestinal fluid secretion stimulated by cholera toxin were examined and compared with those of ramosetron and loperamide. KB-R6933 and ramosetron (0.03-1 mg/kg, p.o.) inhibited the diarrhea induced by 5-HT, but not that by castor oil or prostaglandin E2 (PGE2), in mice. Loperamide significantly inhibited the diarrhea induced by 5-HT, castor oil and PGE2. All drugs tested inhibited the diarrhea induced by restraint stress and the intestinal fluid secretion stimulated by cholera toxin in rats. The results suggest the possibility that KB-R6933 may have clinical efficacy in the treatment of diarrhea.     

Protein kinase C and intestinal fluid secretion: involvement of prostaglandin E2 but not of 5-hydroxytryptamine

To determine the role of protein kinase C in the regulation of intestinal fluid transport, experiments were performed with the rat jejunum in vivo, using the active phorbol ester, 4-beta-phorbol 12-myristate 13-acetate (PMA), as stimulator of protein kinase C. Intraluminally administered PMA dose dependently reversed the net fluid absorption to net fluid secretion and significantly increased prostaglandin E2 (PGE2) but not 5-hydroxytryptamine (5-HT) output into the lumen. Mucosal cyclic AMP levels remained unchanged by PMA. Indomethacin inhibited the increase in PGE2 output and partially reduced the secretory response to PMA. Ketanserin was without effect whereas verapamil totally blocked the secretory response to PMA. It is concluded that intestinal fluid secretion, stimulated by activation of protein kinase C is partly mediated by PGE2 release. PGE2 may facilitate calcium entry rather than increase intracellular calcium through activation of cyclic AMP. Protein kinase C appears to play an important role as an intermediate in phosphoinositol hydrolysis, which is initiated by 5-HT, and finally induces fluid secretion via PGE2.     

Distant intestinal stimulation by cholera toxin in rat in vivo.

Cholera toxin (16 microg/rat) locally administered in the jejunum of anesthetized rats stimulated jejunal secretion and also distant duodenal secretion, as determined with the ligated loop technique. The release of prostaglandin E2 in both jejunal and duodenal secretions and in plasma was increased by cholera toxin, while the release of 5-hydroxytryptamine (5-HT) was unchanged in the early phase of secretion (2 h). The inhibitor of prostaglandin E2 release, indomethacin (10 mg/kg, s.c.), and the 5-HT3 subtype receptor antagonist, granisetron (30 microg/kg i.v.), inhibited the jejunal secretion but had no effect on distant duodenal secretion. However, indomethacin statistically significantly decreased prostaglandin E2 release in both jejunal and duodenal secretions as well as in plasma. The vasoactive intestinal peptide antagonist (VIP-(6-28), 1.2 nmol/100 g h) did not modify jejunal and duodenal secretions. Our study confirmed the local involvement of 5-HT and prostaglandin E2 in choleraic jejunal secretion but not in distant duodenal secretion.     

Regulation of serotonin release from the intestinal mucosa

In the mammalian intestine serotonin (5-hydroxytryptamine, 5-HT) is present in high concentrations in the enterochromaffin cells. The release of 5-HT from the intestinal mucosa is regulated by a complex pattern of neuronal and humoral inputs to the enterochromaffin cells. The enterochromaffin cells appear to be endowed with different inhibitory (alpha 2-adrenoceptors, GABAA- and GABAB-receptors, histamine H3-receptors, receptors for vasoactive intestinal polypeptide and somatostatin) as well as stimulatory receptors (beta-adrenoceptors, muscarine and nicotine receptors). The physiological significance of this complex system of receptors is suggested by experiments which demonstrate that the respective intrinsic neurotransmitters (catecholamines, acetylcholine, GABA and vasoactive intestinal polypeptide) released within the gut are involved in the regulation of the release of 5-HT from the enterochromaffin cells.     

Neurochemistry and neuropharmacology of emesis - the role of serotonin

Emesis is an instinctive defense reaction caused by the somato-autonomic nerve reflex which is integrated in the medulla oblongata. Emesis caused by cytotoxic drugs and radiation is associated with an increase in the concentration of 5-hydroxytryptamine (5-HT) in the intestinal mucosa and in the brainstem. 5-HT released from enterochromaffin (EC) cells, which synthesize and secrete 5-HT, stimulates the 5-HT(3) receptors on the adjacent vagal afferent nerves. This vagal afferent nerve depolarization may evoke the vomiting reflex. This review describes the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release from EC cells and afferent vagus nerve activity.     

Effect of Ganglionic Blocking Compounds on In-vivo Fluid Secretion in the Rat Small Intestine

It is well-known that enteric, secreto-motor nerves mediate cholera toxin-induced fluid secretion in the rat small intestine. This notion is, in part, derived from experiments on anaesthetized animals in which the response to cholera toxin was antagonized by the ganglionic nicotinic receptor antagonist, hexamethonium. In the current study, such anti-secretory action of ganglionic blocking compounds was analysed in an experiment designed to minimize any possible negative effect of general anaesthesia on intestinal secretion. Rats were anaesthetized with ether for 5–10 min, during which time a jejunal loop (10–12 cm) was constructed. The loop was challenged with one of the secretagogues, cholera toxin, prostaglandin E₁ (PGE₁) or okadaic acid. Saline (control) or either of the ganglionic blockers, hexamethonium and chlorisondamine, was administered intravenously. The rats were killed 5 h (cholera toxin) or 1–5 h (PGE₁ and okadaic acid) after challenge, and the amount of fluid accumulated in the loops was determined. Cholera toxin-induced secretion was unchanged by hexamethonium but reduced by approximately 80% by chlorisondamine. The difference in effect between the two blockers might relate to the duration of ganglionic blockade. Chlorisondamine blocked secretion induced by either PGE₁ or okadaic acid by approximately 60%. It is suggested that the anti-secretory effect of ganglionic blocking compounds might be a result of blockade of secreto-motor nerves but other mechanisms, for example interference with haemodynamic factors, cannot be ruled out.     

Chlorpromazine inhibition of enterotoxin-induced fluid secretion and cAMP production in rat ileum

A heat-labile enterotoxin prepared from E. coli (EcLT) increased fluid secretion and cAMP production by segments of rat ileum in vivo and in vitro. The effect of this toxin was compared to that of cholera toxin (VcLT). The increase of cAMP occurred more rapidly after EcLT than after VcLT indicating a difference in the kinetics of uptake action of the two toxins. Chlorpromazine (CPZ) 5 mg/kg given by intramuscular injection 1 h before application of the toxins inhibited the increase in cAMP levels and the increase in fluid secretion in vivo. CPZ 10⁻⁴ M given together with the toxins to intestinal loops in vitro inhibited the increase in cAMP levels and fluid secretion by this preparation. Scanning electron microscopy revealed that CPZ caused extensive shedding of the fluid-producing mucosal cells.     

Autoreceptors can modulate 5-hydroxytryptamine release from porcine and human small intestine in vitro

The effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists were studied on the release of 5-HT from enterochromaffin cells of incubated strips of porcine and human small intestine. Tetrodotoxin (1 μmol/l) was present in the incubation medium to block neuronally mediated inputs to the enterochromaffin cells. The 5-HT_1A receptor agonist (+)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 1 μmol/l) and the 5-HT₂ receptor agonist α-methyl-5-HT (1 μmol/l) increased 5-HT release by 40% in about 60% of the human preparations.These agonists showed no effect on 5-HT release in porcine intestinal mucosa. The 5-HT₃ receptor agonist 2-methyl-5-HT (3–100 μmol/l) increased 5-HT release in both species by 60% (pig) and 90% (man), respectively. These stimulatory effects were antagonized by tropisetron (10 nmol/l). The 5-HT₄ receptor agonist 5-methoxytryptamine (0.3–30 μmol/l) reduced 5-HT release by about 50% in both species. These inhibitory effects were antagonized by tropisetron (3 μmol/l). The basal outflow of 5-HT from the intestinal mucosa was not significantly affected by tropisetron (10 nmol/l; 3 μmol/l). The specific 5-HT₄ receptor antagonist GR 113808 ((1-[2-methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate) (0.1 μmol/l) which by itself did not significantly affect 5-HT release from human duodenal specimens blocked the inhibitory effect of 5-methoxytryptamine (30 μmol/l). These findings indicate that stimulatory 5-HT₃ and inhibitory 5-HT₄ receptors are present on enterochromaffin cells of the porcine and human intestinal mucosa. Under the present experimental conditions endogenous 5-HT does not significantly activate these receptors. Stimulatory 5-HT_1A and 5-HT₂ receptors may additionally be present on human enterochromaffin cells. Received: 19 September 1997/ Accepted: 29 January 1998     

Investigation into the 5-hydroxytryptophan-evoked luminal 5-hydroxytryptamine release from the guinea pig colon

The effect of an endogenous 5-hydroxytryptamine (5-HT) precursor, 5-hydroxytryptophan (5-HTP), on the luminal outflow of 5-HT was examined using the luminally perfused isolated colon of the guinea pig, a model that would facilitate the pharmacological analysis of luminal 5-HT release from enterochromaffin cells (EC cells). 5-HTP (1-10 microM) concentration-dependently caused an increase of the luminal outflow of 5-HT. Either tetrodotoxin (0.3 microM) or atropine (0.2 microM) did not affect the 5-HTP-evoked increase in luminal 5-HT outflow, while the L-type calcium channel blocker, nicardipine (1 microM) or diltiazem (1 microM) reduced the 5-HTP-evoked 5-HT outflow by 47% and 61%, respectively. SB203186 (1 microM), a 5-HT4-receptor antagonist, enhanced the 5-HTP-evoked 5-HT outflow, while ramosetron (1 microM), a 5-HT3-receptor antagonist reduced the stimulating effect of 5-HTP by 66%. Ketanserin (0.1 microM), a 5-HT2A-receptor antagonist did not modify the stimulatory effect of 5-HTP. It is concluded that in the guinea pig colon, 5-HTP facilitates the luminal 5-HT release from EC cells, with no involvement of neuronal mechanisms and a non-neuronal cholinergic system. Furthermore, non-neuronal 5-HT3 and 5-HT4 receptors appear to contribute to the regulation of the luminal 5-HT release evoked by 5-HTP. This new bioassay of the guinea pig colon allows the pharmacological characterization of uncomplicated luminal 5-HT release from EC cells.     

Serotonin and anticancer drug-induced emesis

Cytotoxic drug-induced nausea and vomiting are the side effects most feared by cancer patients. Emesis is an instinctive defense reaction caused by the somato-autonomic nerve reflex, which is integrated in the medulla oblongata. Emesis caused by anticancer drugs is associated with an increase in the concentration of serotonin (5-HT) (5-HT) in the intestinal mucosa and brainstem. 5-HT released from the enterochromaffin (EC) cells, which synthesize and secrete 5-HT, stimulates the 5-HT receptors on the adjacent vagal afferent nerves. The depolarization of the vagal afferent nerves stimulates the vomiting center in the brainstem and eventually induces a vomiting reflex. 5-HT released from EC cells appears to mediate the cisplatin-induced emesis sensitive to 5-HT(3) receptor antagonists. The precise role of 5-HT in the occurrence of vomiting has not been fully elucidated. The present review describes the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release and afferent vagal nerve activity. Various models and methods for predicting emesis are also evaluated.     

The effects of Ca2+ antagonists and hydralazine on central 5-hydroxytryptamine biochemistry and function in rats and mice.

1. The effects of calcium antagonists on behaviour mediated by 5-hydroxytryptamine (5-HT) have been studied in rats and mice together with an investigation of the effects of these drugs on 5-HT synthesis in rat brain and endogenous 5-HT release from brain slices. 2. Administration of felodipine (35 mg kg-1 i.p.) to rats pretreated with tranylcypromine (20 mg kg-1, i.p.) resulted in the animals displaying the complete 5-HT-mediated behavioural syndrome (including head weaving, reciprocal forepaw treading and hind limb abduction) 75 min later. No evidence was obtained for the rate of 5-HT synthesis in brain regions differing between control and felodipine-treated rats. 3. Pretreatment with felodipine (10 or 35 mg kg-1) enhanced the 5-HT-mediated behavioural syndrome induced by injection of tranylcypromine and L-tryptophan. The rate of 5-HT accumulation in the brain was similar in both groups. Administration of Bay K 8644 (1 mg kg-1, i.p.) did not prevent the enhanced behaviour induced by felodipine (10 mg kg-1). 4. The 5-HT behavioural syndrome induced by injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was unaltered by either acute injection of felodipine (35 mg kg-1) or administration of felodipine twice daily for 3 days. 5. Felodipine (10 microM), verapamil (10 microM) and Bay K 8644 (10 microM) did not alter either basal release of endogenous 5-HT from slices prepared from frontal cortex or hind brain, or release following addition of K+ at a concentration of 20 mM, or 35 mM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification of new small molecule inhibitors of cystic fibrosis transmembrane conductance regulator protein: in vitro and in vivo studies

Cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-regulated chloride channel that has been proposed as a pharmacological target to reduce intestinal fluid loss in cholera. The aim of this study was to identify new CFTR inhibitors by high-throughput screening. Screening of 50,000 drug-like small molecules was performed using a cell-based assay of iodide influx in Fisher rat thyroid (FRT) cells co-expressing human CFTR and halide-sensitive yellow fluorescent protein (YFP-H148Q). Two new CFTR inhibitors, 2-[N-(3-hydroxy-4-carboxyphenyl) amino]-4-(4-methylphenyl)-thiazole (INH 1) and 1-acetyl-5-bromo-2,3-dihydro-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-Indole-7-sulfonamide (INH 2), were identified. They were then determined for potency, reversibility and specificity by electrophysiological methods, and for in vivo efficacy in mouse model of cholera toxin-induced intestinal fluid secretion. INH 1 and INH 2 reversibly inhibited cAMP-activated apical chloride current in FRT cells with Kis of 15 and 20 microM, respectively. Similarly, in short-circuit current analysis in human colonic epithelial cell lines (T84 cells), cAMP-activated chloride secretion was inhibited by INH 1 and INH 2 with Kis of 24.5 and 25.3 microM, respectively. Calcium-activated chloride secretion in the T84 cells was markedly inhibited by 100 microM of INH 1, but was unaffected by 100 microM of INH 2. In vivo studies in mice showed that a single intraperitoneal injection of INH 1 (3 mg/kg) reduced cholera toxin-induced intestinal fluid secretion by 40%, whereas INH 2 produced no effect. Our results indicate that INH 1 could be a new class candidate for a blocker of cholera toxin-induced intestinal fluid secretion as well as a CFTR inhibitor.     

Enhancement of vasoconstrictor and attenuation of vasodilator effects of 5-hydroxytryptamine by the calcium channel blockers nimodipine and nifedipine in the pig

As calcium (Ca2+) channel blockers are effective against the vasoconstrictor responses to 5-hydroxytryptamine (5-HT) in vitro, and a favourable response is claimed for these drugs in migraine prophylaxis, we studied the interaction between nimodipine or nifedipine, and 5-HT for effects on carotid haemodynamics in the anaesthetized pig. Intracarotid infusions of nimodipine (0.25 microgram X kg-1 X min-1), nifedipine (0.75 microgram X kg-1 X min-1) or 5-HT (2.0 micrograms X kg-1 X min-1) caused a redistribution of carotid blood flow in favour of the nutrient (capillary) fraction at the expense of the non-nutrient (arteriovenous anastomoses; AVA) fraction. Compared to those of 5-HT, the effects of the Ca2+ channel blockers on cranial AVAs were much weaker and the increase in the capillary fraction was observed mainly in the skeletal muscles, rather than in the skin and ears as with 5-HT. When 5-HT was infused in the presence of nimodipine or nifedipine, the amine-induced vasoconstrictor responses in the total carotid vascular bed and its AVA fraction were either not attenuated or were increased while the vasodilator responses were reduced. We conclude that: in contrast to what was found in vitro, the 5-HT-induced vasoconstriction in vivo, involving either '5-HT1-like' (AVAs) or 5-HT2 (arterioles) receptors, was not antagonized by nimodipine or nifedipine; the attenuation of the 5-HT-induced dermal vasodilatation by the two Ca2+ channel blockers is most likely to be the result of a 'steal' due to the profound vasodilatation in the skeletal muscle region; and the comparatively mild reduction in AVA conductance caused by the Ca2+ channel blockers may be one of the reasons for their inability to abort acute attacks of migraine. The increase in nutrient blood flow is of potential benefit, but whether this property of the Ca2+ channel blockers is linked to their usefulness in migraine prophylaxis remains to be ascertained.     

Effect of vasoactive intestinal polypeptide on the release of serotonin from the in vitro vascularly perfused small intestine of guinea pig

Summary Isolated segments of the guinea pig small intestine were vascularly perfused and the release of endogenous serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) into the portal vein was measured. All test substances were intraarterially perfused. Vasoactive intestinal polypeptide (VIP, 1 pmol/l — 100 nmol/1) inhibited the spontaneous release of 5-HT and 5-HIAA. The maximal inhibitory effect (about 60%) was seen at 100 pmol/1. The effect of VIP on the spontaneous release of 5-HT and 5-HIAA was not changed in the presence of 1 ol/l tetrodotoxin (TTX).Raising intraluminal pressure by 500 Pa for 5 min increased the release of 5-HT and 5-HIAA by about 25%. Raising the intraluminal pressure in the presence of VIP reduced the release of 5-HT and 5-HIAA by about 75%. In the presence of TTX (1 gmol/l), raising intraluminal pressure also caused a decrease of the release of 5-HT and 5-HIAA which was unaffected by the additional presence of VIP. The fluid volume expelled during peristaltic activity was not affected by VIP, but reduced by about 90% in the presence of TTX.In conclusion the results demonstrate a direct inhibitory effect of VIP on the release of 5-HT from the enterochromaffin cells. In addition, VIP appears to interfere with the neuronally mediated stimulation of 5-HT release during peristaltic activity. Send offprint request to H. Schwörer at the above address     

低浓度非洛地平对豚鼠右心室乳头肌动作电位的影响

用细胞内微电板方法研究低浓度非洛地平对豚鼠右心室乳头肌动作电位的作用。非洛地平０．１，１ｎｍｏｌ·Ｌ－１对动作电位无作用。但在５ｎｍｏｌ·Ｌ－１时，非洛地平可明显延长动作电位时程。延长作用的起效时间为５ｍｉｎ，作用持续６０ｍｉｎ以上。用台氏液冲洗可使非洛地平的延长作用消失。非洛地平５ｎｍｏｌ·Ｌ－１和３μｍｏｌ·Ｌ－１对动作电位时程具有低浓度延长，高浓度缩短的双相作用。硝苯地平１ｎｍｏｌ·Ｌ－１可明显延长动作电位时程，但维拉帕米０．１．１和５ｎｍｏｌ·Ｌ－１对动作电位无明显作用。这表明低浓度激动心肌钙通遁可能是二氢吮嚏矣钙拮抗剂的共性，但不是所有钙拮抗剂的共性。