Acute effects of aflatoxins on guinea pig isolated ileum.

Previous studies on the aflatoxins have focused mainly on their chronic toxic effects. In this study we investigated the acute gastrointestinal effects of four common aflatoxins on isolated guinea pig ileum. AFB(1) (EC(50) 4.6+/-0.4 microM) and AFB(2) (EC(50)17+/-4.4 microM) contracted isolated guinea pig ileum in a dose-dependent manner, whereas AFG(1) and AFG(2) evoked no contractions. Atropine (5.9 nM 11.8 and 23.6 nM) antagonized AFB(1)-induced contractions in a dose-dependent manner. Pretreatment with the nicotinic ganglionic blocker, hexamethonium (up to 55 microM), left AFB(1)-induced contractions unchanged. In contrast, tetrodotoxin (0.3 microM), blocked AFB(1) contractile activity. The two inhibitors of ACh release, morphine (0.3 microM) and clonidine (0.4 microM), antagonized EC(50) AFB(1)-induced contractions, and apamin, a drug that increases neuronal excitability, facilitated the EC(50) AFB(1)-induced contractile effect. The choline uptake blocker, hemicholinium (17.4 microM) markedly reduced AFB(1)-induced contractions. These results suggest that aflatoxins induce their contractile effect indirectly through the cholinergic system by stimulating acetylcholine release from the postganglionic parasympathetic nerve endings. The acute actions of aflatoxins on isolated guinea pig ileum could explain their acute gastrointestinal effects in humans and animals.     

Prevention of promethazine-induced gastric ulcers in guinea pigs with disodium cromoglycate

The preventive effect of different doses of disodium cromoglycate (DSCG) on promethazine-induced gastric ulceration in guinea pigs was determined. Doses of 12.5 mg/kg of DSCG or higher (up to 200 mg/kg) caused a 35% reduction in promethazine-induced gastric ulceration. The incidence of inhibition of ulcer formation was not dose-dependent. With a dose of 200 mg/kg of cromoglycate alone administered intraperitoneally, gastric ulcers did not occur.     

Histamine receptors in the guinea pig ileum

Summary Histamine and some related compounds acting selectively on H₂-or H₁-receptors were tested for their ability to contract the guinea pig ileum, in the usual whole ileum preparation and in the longitudinal muscle preparation. The concentrations elicited by histamine in both kinds of preparations were not potentiated by cimetidine or metiamide and were not inhibited by administration of H₂ receptor selective agonists in doses which were subthreshold for contracting the guinea pig ileum; higher doses of the H₂ agonists could actually potentiate the effect of histamine. The results obtained suggest that H₂ receptors with relaxing effect do not occur in the guinea pig ileum or at least that they are not involved in the contraction of the longitudinal muscle layers. The possibility that a sub-type of H₂ receptors with properties different from those of the classical H₂ receptors so far known, exists in the guinea pig ileum, cannot be excluded.     

Effect of ethacrynic acid on guinea pig ileum

The effect of ethacrynic acid on the motor function of guinea pig ileum was studied in vitro. Ethacrynic acid produced dose-related (5-160 microgram/ml) contractions in this tissue. Morphine, tetrodotoxin and sodium-free medium prevented the contractions while hexamethonium, diphenhydramine, methysergide or indomethacin did not. Atropine in a high concentration (0.1 microgram/ml) only inhibited the contractions. Ethacrynic acid inhibited the contraction of ileum induced by electrical stimulation of intramural nerves. This was not prevented by pretreatment with reserpine. Repeated exposure to ethyacrynic acid developed tachyphylaxis in contractile response. Inhibition of electrically elicited contraction of guinea pig ileum also diminished with repeated treatment. Ethacrynic acid (80-160 micrograms/ml) inhibited the peristaltic reflex of the guinea pig ileum. It is concluded that the excitatory effect of ethacrynic acid is most probably mediated by the release of neurotransmitter, however, the mechanism of the inhibitory effect remains to be elucidated.     

Cytoprotective effects of disodium cromoglycate on rat stomach mucosa.

The cytoprotective effects of the anti-asthmatic drug, disodium cromoglycate (DSCG), on gastric mucosal necrosis induced by ethanol in rats were studied. Subcutaneous, but not oral, DSCG prevented the formation of gastric lesions and this effect was dose-dependent between 1.25 and 40 mg kg-1, with an ED50 value of 6.8 mg kg-1. Maximal cytoprotection occurred 15-30 min after DSCG treatment. Histological examination revealed that DSCG effectively protected the gastric mucosa against ethanol-induced vascular congestion, haemorrhage, epithelial desquamation and mucosal oedema. Enhanced production of endogenous prostaglandins, which are known cytoprotective compounds, could not explain the mucosal protection. At a dose of 40 mg kg-1, DSCG did not change prostaglandin E2 or 6-keto-prostaglandin F1 alpha concentrations in gastric mucosal tissue, although its cytoprotective activity was partially inhibited by prior treatment of the animals with indomethacin.     

干酪菌发酵产物对豚鼠离体回肠平滑肌收缩功能的影响

目的 观察干酪菌发酵产物对豚鼠离体回肠平滑肌收缩功能的影响。方法采用豚鼠离体回肠平滑肌标本,观察加入干酪菌发酵产物前后肌紧张的变化以及加入几种受体阻断剂对其药效的影响。结果 干酪菌发酵产物能提高豚鼠离体回肠平滑肌肌紧张,且呈剂量-效应依赖关系,组织胺H1受体阻断剂苯海拉明能阻断其兴奋作用。结论 干酪菌发酵产物能提高豚鼠离体回肠平滑肌肌紧张,其作用途径与组织胺H1受体有关。     

Contractile effect of prolactin on guinea pig isolated ileum

Prolactin (PRL) at high concentrations contracted the guinea pig isolated ileum. The maximum response elicited by PRL was 44% of that of histamine-induced responses. There was no significant difference in potency between PRL preparations obtained from two different sources. PRL responses were nullified by denaturation or proteolytic digestion of the hormone. The contractile response was antagonised by atropine and potentiated by neostigmine, but unaffected by the prostaglandin antagonist SC-19220. The pA2 values of atropine against PRL and ACh were similar. Preincubation with morphine, which inhibits ACh release, produced slight inhibition of PRL-evoked contractions. Even high concentrations of PRL failed to produce any response in neostigmine-treated frog rectus muscle preparations. This suggests that PRL may produce contractions through a cholinergic mechanism involving muscarinic receptors. Enhanced gut motility reported earlier for hyperprolactinemic states may be attributed to this cholinomimetic effect of PRL on the intestinal tract.     

X-ray analysis of disodium cromoglycate

X-ray crystallographic studies have been made on the anti-asthmatic drug disodium cromoglycate. Interesting features of the structure are the non-coplanarity of the chromone (benzopyrone) rings, an apparent disorder in the position of one of the sodium atoms, and the occurrence of water-filled ‘channels’ in the crystal lattice.     

Temperature-dependent effects of increased intraluminal pressure on serotonin release from the vascularly perfused guinea pig ileum

Summary Isolated segments of the guinea pig ileum were vascularly perfused and the release of endogenous serotonin into the portal effluent was measured. Peristalsis was induced by raising the intraluminal hydrostatic pressure by 500 Pa for 5 min. Serotonin release increased during peristalsis induced by fluid of 37°C, but decreased when the temperature of the intraluminal fluid was between 13°C and 22°C. In the presence of naloxone (0.3 mol/l) raising the intraluminal pressure with fluid of 37°C caused an inhibition of the serotonin release which was blocked by scopolamine (0.1 mol/l). Naloxone did not affect the inhibition of Serotonin release during peristalsis caused by fluid of 19°C, neither did indometacin (1 mol/l). In conclusion, liquid distension of the guinea pig isolated ileum elicits peristaltic activity, and affects the release of serotonin into the portal circulation. The changes in serotonin release depend on the temperature of the fluid passing through the intestinal lumen, whereas peristalsis is not affected by the temperature of the intraluminal fluid.Abbreviations 5-HT 5-hydroxytryptamine - 5-HIAA 5-hydroxyindoleacetic acid Send offprint requests to H. Schworer     

Comparative studies on anti-nicotinic action of hexamethonium, mecamylamine and adenosine in the guinea pig isolated ileum

The mechanism of anti-nicotinic actions of hexamethonium, mecamylamine and adenosine was investigated in guinea pig isolated ileum. Mecamylamine shifted the dose-response curves for nicotine to the right with a gradual depression. On the other hand, hexamethonium shifted the curves to the right without a depression and adenosine made only a gradual depression, suggesting the different modes of their antinicotinic actions. The transmurally-stimulated twitch response was unaffected, partially inhibited and abolis hed by hexamethonium, mecamylamine and adenosine, respectively. These three compounds also had little effect on direct muscle response to acetylcholine and on the acetylcholinesterase activity of the ileum. From these results, it is suggested that the antagonism to the effect of nicotine shown by mecamylamine does not appear to be a simple competitive blockade of ganglionic receptors as is the case with hexamethonium and that adenosine may antagonize the effect of nicotine non-competitively. The mechanism by which mecamylamine and adenosine showed anti-nicotinic action is discussed.     

Smooth muscle relaxing drugs and guinea pig ileum

The effects of various smooth muscle relaxing drugs on contractile responses to acetylcholine (ACh), Ba2+ and Ca2+, and on the tissue cyclic AMP levels were examined in the guinea pig ileum. Papaverine and theophylline caused a decrease both in the maximum height and the slope of dose-response curves induced by the three stimulants, and an increase in the cyclic AMP levels. Diltiazem and D-600 produced a decrease in the maximum and the slope of ACh and Ba2+ dose-response curves, shifted the Ca2+ dose-response curves to higher concentrations, in a parallel manner, but failed to change the cyclic AMP levels. Etomidoline and benactyzine shifted the curves for the three stimulants in parallel to the right, but at higher concentrations depressed the maximum of ACh and Ba2+ responses with a further parallel shift. These drugs exerted little influence on the basal level of tissue cyclic AMP, but etomidoline significantly depressed the Ba2+ -induced increase in cyclic AMP level. The smooth muscle relaxing drugs used could be classified in three types, thereby suggesting that there are at least three different mechanisms involved in smooth muscle relaxing action.     

Desensitization of the isolated guinea pig ileum to antihistaminic agents

Guinea pig ileum developed in vitro a progressive desensitization to the antihistaminic agents mepyramine and benadryl. This desensitization had uncommon characteristics: (1) at the 6.5-9 h period of the experiments, it consisted only of a decreased rate of action of the drugs (1.66 fold and 2 fold increases in the 2 min Kb value of mepyramine and benadryl respectively), without variation in the equilibrium Kb values; (2) it was not a drug effect since control strips (strips exposed to the first dose of antihistaminic agent after 5.5 h in vitro) also showed a decreased rate of action of the drugs (1.58 fold and 1.6 fold increases in the 2 min Kb value of mepyramine and benadryl respectively), without variation in the Kbe values. The desensitization also did not depend on the bathing medium or on the amount of available histamine receptors. The only explanation of the desensitization is a slowing in the antihistaminic agent-receptor reaction either in its access stage or less probably in its interaction stage.     

Opioid effects of short enkephalin fragments containing the Gly-Phe sequence on contractile responses of guinea pig ileum

1. Effects of the fragments H-Gly-Phe-OH, H-Gly-Phe-NH₂ or H-Gly-Phe-OMe on the electrically stimulated cholinergic contractions of the longitudinal layer in isolated guinea pig ileum and on the Morphine-, Met-enkephalin- or Leu-enkephalin-induced inhibition of these contractions were analyzed for opioid activity in respect to Gly-Phe sequence.2. H-Gly-Phe-OH or H-Gly-Phe-NH₂ exerted no effects, while H-Gly-Phe-OMe applied cumulatively (1 pM-1 mM), concentration-dependently reduced the contractions to electrical stimulation, the IC₅₀ value being 1.96 ± 0.06 μM. Naloxone (1–5 μM) did not reverse the H-Gly-Phe-OMe effects.3. H-Gly-Phe-OMe at single concentrations (1–10 μM) significantly decreased the maximum inhibition produced by cumulatively added (0.1 nM-100 μM) morphine, Met-enkephalin or Leu-enkephalin. The regression lines for the opioids were shifted to the right but not always in a parallel fashion; the IC₅₀ values were higher as compared to the controls and lower as compared to the IC₅₀ values after naloxone.4. The pA₂ value for H-Gly-Phe-OMe with respect to morphine (6.43 ± 0.14) did not differ from that to Met-enkephalin (6.68 ± 0.35) or Leu-enkephalin (9.06 ± 0.98); the slope of the pA₂ plot to morphine was near unity.5. These data indicated that H-Gly-Phe-OMe exerted predominantly a potent non-competitive opioid antagonistic effect suggesting that short enkephalin fragments containing the Gly-Phe sequence might possess an opioid activity.     

Effect of l-ephedrine on cholinergic neurotransmission in the isolated guinea pig ileum

In the isolated guinea pig ileum, the effects of I-ephedrine on the twitch response to field stimulation were investigated in the presence of propranolol. Ephedrine and clonidine inhibited the twitch response but not the contraction to exogenous acetylcholine. The inhibitory effect of clonidine was significantly diminished by yohimbine pretreatment. However, the inhibitory effect of ephedrine was not influenced by yohimbine, sulpiride or 6-hydroxydopamine (6-OHDA) pretreatment. Most of this action of ephedrine appeared to be cholinergic prejunctional in nature, but unrelated to activation of prejunctional alpha 2-adrenoceptors and dopamine sensitive receptors on the cholinergic nerves in this preparation.     

Effects of dapiprazole on contractile responses of guinea pig isolated ileum

The effects of dapiprazole, a relatively new alpha 1-adrenolytic agent, on contractile responses and on spontaneous mechanical activity were studied in guinea pig isolated ileum. Dapiprazole (10(-10) to 10(-4) M) produced a concentration-dependent inhibition of high K+ (80 mM) -induced contractions. These inhibitory effects were observed with dapiprazole added either before or after the induced contractions. The Ca2+-induced contractions of K+-depolarized ileum were also inhibited by dapiprazole. Dapiprazole inhibited in a non competitive manner the responses of the ileum to: carbachol, histamine, 5-hydroxytryptamine, pentagastrin, angiotensin II and cholecystokinin. In order to analize whether dapiprazole exerts an intracellular effect on Ca2+-store, skinned preparations were used. The results suggest that dapiprazole might inhibit Ca2+ entry through both voltage-and receptor-operated channels of the smooth muscle membrane.