Calcium channel antagonists and gastrointestinal function.
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Animals↗
Biomedical subjects
G B Glavin
Publications and source records attributed to G B Glavin.
Characterization of the gastroprotective effects of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine hydrochloride, a non-H1/non-H2 histamine antagonist.
N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl (DPPE) is an antihistamine with a unique profile of activity in the stomach. It is antisecretory and blocks the formation of experimental cold/stress- and ethanol-induced gastric lesions, as well as cysteamine-induced duodenal ulcers in a fashion more potent than observed with histamine H2 antagonists such as cimetidine. We now demonstrate that the antiulcer effects of DPPE are associated with a dramatic (10-fold) rise in the stable prostacyclin hydration product 6-keto-prostaglandin F1 alpha in gastric secretion collected from conscious rats. Cyclooxygenase inhibitors such as acetylsalicylic acid, indomethacin and sodium meclofenamate abolish high-dose DPPE-induced gastroprotection, whereas sodium salicylate, a lipoxygenase inhibitor, does not. These data suggest that DPPE-induced gastroprotection is mediated, at least in part, through an increase in endogenous prostacyclin (prostaglandin I2) synthesis in the gastric mucosa. These data are not consistent with an effect of DPPE primarily at the H2 receptor, but are consistent with the recent suggestion that DPPE antagonizes histamine at HIC, an intracellular histamine site.
6-Ketoprostaglandin F1 alpha↗
Gastrointestinal effects of contaminated mussels and putative antidotes thereof.
A recent outbreak of amnesic shellfish poisoning (ASP) in Atlantic Canada was characterized by severe gastrointestinal and central nervous system pathology. We examined the gastrointestinal effects of an acidic extract of blue mussels contaminated with domoic acid, the suspected toxin responsible for the ASP. We also tested the gastric effects pure domoic acid as well as a putative antagonist of neuroexcitant amino acid receptors, kynurenic acid. Mussel extract produced gastric (antral) ulcers, duodenal ulcers, gastric and duodenal hyperemia and bleeding, as well as peritoneal ascites. Kynurenic acid protected significantly against extract-induced gastropathy, particularly when given 60 or 75 minutes after extract. Pure domoic acid resulted in fatalities in all infant mice tested. These animals exhibited gastric bleeding and hemorrhage, especially at the higher doses employed. In otherwise untreated rats, kynurenic acid exerted significant anti-stress ulcer and anti-gastric secretory effects, but was less effective at blocking ethanol-induced gastric lesions. We suggest that there may be both peripheral as well as central effects of kynurenic acid in modulating normal and pathological gastric function.
Animals↗
Sensitive murine model and putative antidotes for behaviorial toxicosis from contaminated mussel extracts.
The recent outbreak of "amnesic" mussel poisoning syndrome, attributed to domoic acid contamination of edible mussels claimed several lives and left many victims impaired with a peculiar loss of memory. We administered the whole mussel extract (WMX) and the mussel hepatopancreas extract (MHX, hepatopancreas being the major site for sequestration of domoic acid in mussels) in Swiss-Webster mice. A characteristic syndrome featuring sluggishness, scratching stereotypy, convulsions and death was noticed. Infant mice were some 3- to 4-fold more sensitive to the WMX toxicity. Kynurenic acid (KYN), an endogenous nonselective excitotoxin antagonist offered significant protection against the toxicosis after its onset had been provoked by the mussel extract. This observation emphasizes the feasibility of using KYN or related compounds in the therapy of poisoning from excitotoxins. As a logical extension of this possibility we examined the possibility that endogenous KYN could be exploited for similar protection against domoate toxicosis in our murine model. The time frame during which KYN was protective was increased by probenecid, a blocker of organic acid transport and by tryptophan, a precursor of endogenous KYN. We examined also the classical anticonvulsants phenytoin and ethosuximide, as well as dextromethorphan at its excitotoxin antagonistic dose. The infant mouse model of domoate-toxicity holds promise for being developed into a rapid, sensitive, reliable and inexpensive biological assay for screening commercial batches of mussel for excitotoxin contamination. Kynurenic acid and dextromethorphan should be further examined as antidotes for possible therapeutic use in existing victims and in the treatment of future domoate toxicosis occurring here or elsewhere.
Age Factors↗
Opioid involvement in epileptogenic and neurovisceral activity.
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3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Calcium channel modulators: effects on gastric function.
Calcium is important in stimulus-secretion coupling in the gut. We therefore examined a dihydropyridine (nitrendipine), a phenylalkylamine (verapamil) and a benzothiazepine (diltiazem) calcium channel blocker as well as a calcium channel 'agonist', CGP 28392, in several models of gastric function. Nitrendipine significantly decreased stress-induced gastric lesions, but was far less efficacious against 100% ethanol-induced lesions. The anti-ulcer effects of nitrendipine were not reversible with indomethacin, sodium meclofenamate or N-ethylmaleimide. Nitrendipine also significantly reduced basal gastric acid output. Verapamil significantly reduced stress lesions in an indomethacin and meclofenamate-reversible manner, but worsened ethanol ulcers. Verapamil also decreased basal acid secretion. Diltiazem decreased stress lesions (indomethacin- and meclofenamate-reversible), worsened ethanol lesions and slightly reduced acid secretion. CGP 28392 exerted a modest stress gastroprotective effect, decreased ethanol lesions and reduced slightly basal acid secretion. A possible clinical role for gastric calcium channel blockade is raised by these results.
Animals↗
Potential therapeutic effect of nitrendipine.
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Animals↗
Stress-rest cyclicity in the pathogenesis of restraint-induced stress gastric ulcers in rats.
Temporal patterns of stress and rest have been shown to influence extent of shock-induced pathology. In the present study, the influence of stress-rest cycles was studied on amount of gastric ulceration after two forms of immobilization stress in rats. In Experiment 1, rats were subjected to different patterns of cold supine restraint interspersed with rest periods. A single 180 minute exposure produced more extensive ulceration than did a series of six 30 minute stress periods interspersed with 30 minute rest periods in the home cage. Different results were found in Experiment 2 using the stress of restraint in water and stress/rest patterns parallel to those used in Experiment 1. Previous reports have suggested that a "priming" stress might activate mechanisms protective against gastric ulceration. This was also investigated in Experiment 2 when animals were subjected to either a single 150 minute stress period, a 30 minute priming exposure to the same stressor 150 minutes prior to a 150 minute second exposure, or a 30 minute priming exposure 30 minutes prior to a 150 minute second exposure. No evidence was found for protective effects. In fact, a priming stress 30 minutes prior to final exposure enhanced ulceration. The studies provide some supporting evidence for the role of cycles in determining extent of stress pathology. Such data must be accounted for in any description of the mechanisms of stress-related ulceration.
Animals↗
Mussel poisoning and excitatory amino acid receptors.
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Animals↗
Neurotoxicity and lethality of toxic extracts from Atlantic coast shellfish.
1. HCl-extract of poisonous shellfish was injected i.p. into Swiss-Webster mice. 2. Behavioral effects (sluggishness, scratching, huddling, clonic convulsions, respiratory distress and mortality) were noted. 3. Infant mice were more sensitive than were the adults to XTRT toxicity. Estimated LD50 values were; adult: 34.8 ml/kg i.p., infant: 9.6 ml/kg i.p. 4. The mouse model of shellfish-toxicity offers the advantages of a degree of similarity with the human clinical situation and a rapid time course for screening antagonists against shellfish poisoning.
Aging↗
Kynurenic acid protects against gastroduodenal ulceration in mice injected with extracts from poisonous Atlantic shellfish.
1. Mice were treated with an extract prepared from poisonous Atlantic mussels. 2. Gastric and duodenal ulcers, duodenal hyperemia and peritoneal ascites resulted from administration of the shellfish extract, with an LD84 of 1.0 ml. 3. Kynurenic acid, an antagonist at excitatory amino acid receptors, protected significantly against gastroduodenal ulcers, ascites and hyperemia when given at 60 or 75 min post-extract. 4. It is likely that the gastrointestinal damage evoked by this extract is due to its domoic acid content and that kynurenic acid may prove useful against domoic acid-induced gastropathy.
Animals↗
Kynurenic acid protects against neurotoxicity and lethality of toxic extracts from contaminated Atlantic coast mussels.
1. An aqueous acidic extract from poisonous Atlantic coast mussels was injected i.p. into groups of Swiss-Webster mice at the LD84 value (= 40 ml of extract/kg). Body-scratching, clonic convulsions and death were consistently observed in response to XTRT injection. These results are consistent with the presumed presence of the neuroexcitant amino acid, domoic acid, in the contaminated mussels. 2. Kynurenic acid at 300 and 600 mg/kg i.p. protected powerfully and significantly against extract-induced neurotoxicity. Greatest protection was observed when the antidote was administered between 30 and 90 min after injection of the toxic extract.
Animals↗
A study of monoamine metabolism in human epilepsy.
Fourteen patients with intractable epilepsy underwent surgical resection of their epileptogenic focus. Hippocampal and temporal cortical samples were obtained, and subjected to high performance liquid chromatography with electrochemical detection. Levels of 5-hydroxyindoleacetic acid (5-HIAA) in actively spiking temporal cortex were 0.454 +/- 0.012 ng/mg (mean +/- SEM), contrasting with less actively spiking cortex values of 0.248 +/- 0.042 ng/mg and normal literature values, obtained from post-mortem material, of 0.140 +/- 0.050 ng/mg. Similarly, homovanillic acid (NVA) levels were significantly increased in epileptic tissue compared to normal literature values. Actively spiking cortex values were 0.172 +/- 0.001 pg/mg, less active cortex values were 0.058 +/- 0.012 pg/mg, and literature values were 0.011 +/- 0.002 pg/mg. Although a direct statistical comparison between the data reported here and literature values may not be valid, the findings show a continuum from normal through increasingly active electrode sites, likely reflecting a true biologic phenomena. Similarly, statistically significant increases in 5-HIAA and HVA levels were found in hippocampal tissue, which also showed significantly lower dihydroxyphenylacetic acid levels. We conclude that raised levels of serotonin and dopamine metabolites in actively spiking cortex likely reflect an increase in their turnover, and are an epileptic epiphenomenon. Exaggeration of turnover may represent the "metabolic noise" of epilepsy, rather than a concerted strategy of local or distal neurons to contain an epileptogenic focus.
3,4-Dihydroxyphenylacetic Acid↗
Activity of selective dopamine DA1 and DA2 agonists and antagonists on experimental gastric lesions and gastric acid secretion.
Selective dopamine (DA) DA1 and DA2 receptor agonists and antagonists were examined for their effects on cold-stress gastric lesions, 100% ethanol gastric lesions and basal gastric acid secretion. The selective DA1 agonist SKF 38393 [R-(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol.HCl] attenuated cold-stress and ethanol lesions and blocked basal acid output. The protective effects of SKF 38393 were reversed by the cyclooxygenase inhibitors indomethacin, sodium meclofenamate, by the peripherally selective DA receptor antagonist domperidone and by the tissue sulfhydryl blocker, N-ethylmaleimide. The DA1 antagonist, SCH 23390, worsened lesion formation and augmented gastric acid secretion. N-0437 [S-(-)-2-N-propyl-N-2-thienylethylamino)-5-hydroxytetralin], a DA2 agonist, was less potent than SKF 38393 at reducing experimental gastric lesion formation, but slightly more potent at attenuating gastric secretion. The DA2 antagonist, eticlopride, was inactive in all models. Based upon these in vivo data, we suggest that: 1) the gut DA receptor may be of the DA1 subtype and 2) that activation of gut DA1 receptors produces gastroprotection by several mechanisms, at least one of which is by reducing gastric acid output.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Kynurenic acid attenuates experimental ulcer formation and basal gastric acid secretion in rats.
Kynurenic acid is a broad spectrum antagonist at neuroexcitant amino acid receptors in the mammalian brain. Preliminary data indicated that kynurenic acid attenuates domoic acid-induced central nervous system pathology, lethality and gastrointestinal pathology. We now show that kynurenic acid significantly blocks restraint-cold stress ulcers, ethanol ulcers and basal, non-stimulated gastric acid secretion in normal rats not subjected to neurotoxin challenge. There may be peripheral actions, in addition to the central effects of kynurenic acid, in modulating normal and pathological gastric function.
Animals↗
Influence of rearing conditions on voluntary ethanol intake and response to stress in rats.
The effects of exposure to four environmental rearing conditions on subsequent voluntary ethanol intake and response to immobilization stress were examined. Male weanling rats were reared in an enriched environment, with a female partner, with a male partner, or individually, for 90 days. At 111 days of age, voluntary consumption of ethanol in increasing concentrations (3 to 9%, v/v) was assessed. Following the ethanol-exposure period, rats were randomly divided into stressed and nonstressed groups and exposed to 3 h of immobilization. Results indicated that the enriched animals consumed greater amounts of ethanol as compared to all other groups, suggesting that the enriched environment and not handling, housing conditions, or the presence of another male or female is responsible for the observed increase in ethanol drinking behavior. Ulcer data indicated that among environmentally enriched rats, ethanol attenuated stress ulcer development relative to their non-ethanol-exposed but stressed controls. In nonstressed enriched rats, ethanol alone exacerbated stomach damage. We suggest that environmental rearing conditions markedly influence the complex interaction between ethanol intake and the response to stress.
Alcohol Drinking↗
Verapamil and nifedipine effects on gastric acid secretion and ulcer formation in rats.
The calcium channel antagonists verapamil and nifedipine were examined for their effects on conscious basal gastric acid output, stress ulcer formation and on ethanol-induced ulcers. Both compounds significantly reduced gastric acid secretion, however verapamil did so in a dose-related manner. Both verapamil and nifedipine significantly attenuated stress gastric ulcer formation. Nifedipine, at a dose of 32.0 mg kg-1, virtually abolished stress ulcers. Verapamil exacerbated, while nifedipine, at 32.0 mg kg-1, attenuated ethanol-induced gastric ulcers. The differential gastrointestinal effects of these calcium channel antagonists support the existence of multiple classes of calcium channels in the gut and suggest an important role for intracellular calcium and hence, its blockade, in gastric pathophysiology.
Animals↗
Antiulcerogenic and antisecretory effects of a novel diphenylmethane derivative and antiestrogen binding site ligand.
N,N-Diethyl-2-[4-(phenylmethyl)-phenoxy]-ethanamine hydrochloride (DPPE) is a para-diphenylmethane derivative that binds selectively and with high affinity to the microsomal antiestrogen binding site (AEBS). Recent studies with DPPE indicate that AEBS is closely related to a lower affinity non-H1, non-H2 histamine site that may be associated with calcium channels; the DPPE-AEBS site is different from that which verapamil binds, however, DPPE, but not verapamil, demonstrates antiproliferative effects in vitro and is antiestrogenic in vivo. We now show that DPPE profoundly inhibits restraint and cold stress and ethanol-induced gastric ulcer formation, accelerates ulcer healing, attenuates the stress-induced rise in plasma corticosterone level, and significantly reduces basal and H2 agonist (dimaprit)-stimulated and, to a lesser extent, bethanechol-stimulated gastric acid output in conscious rats. A nonulcerogenic but prostaglandin-depleting dose of indomethacin completely blocks the inhibitory effects of DPPE on stress ulcer formation. Conversely, verapamil only slightly attenuates dimaprit-stimulated gastric acid secretion and exacerbates ethanol-induced gastric ulcers; its anti-stress ulcer effects are only partially attenuated by indomethacin. These findings support the likelihood that the site of action of DPPE is different from that of verapamil, and that an effect on prostaglandins may, at least in part, contribute to its antiulcer and apparent cytoprotective effects.
Animals↗