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PubMed1990

Effects of oxygen deficiency and calcium omission on carbon tetrachloride hepatotoxicity in isolated perfused livers from phenobarbital-pretreated rats.

The effect of oxygen concentration and Ca2+ omission on CCl4-induced hepatotoxicity was studied in a non-recirculating and hemoglobin-free liver perfusion system using phenobarbital-pretreated rats. With 95% O2-saturated perfusate, infusion of 0.5 mM CCl4 caused an instantaneous increase of thiobarbituric acid reactive substances (TBA-RS) in the effluent perfusate, accompanied by only a slight leakage of K+ and lactate dehydrogenase (LDH). CBrCl3 produced a far greater increase in the TBA-RS level, but again with slight K+ and LDH leakage. With 20% O2-saturated perfusate, CCl4 caused a marked LDH leakage, which was preceded by an early and considerable increase in K+ leakage coupled with Na+ uptake, Ca2+ uptake was initially slight, being enhanced concurrently with the LDH leakage. The TBA-RS level changed biphasically with an initial moderate and a succeeding greater increase coupled with LDH leakage. N,N"-Diphenyl-p-phenylenediamine and promethazine suppressed the TBA-RS production, but improved neither K+ nor LDH leakage. Omission of the Ca2+ from the perfusate reduced the initial K+ leakage as well as the later TBA-RS release, and markedly delayed the LDH leakage. In retrograde perfusion under low oxygen supply with Ca2+, CCl4 produced essentially the same toxic manifestations as those observed in the anterograde perfusion. Hepatocytes of the periportal and pericentral areas were not stained with trypan blue in the antero- and retrograde perfusion systems respectively. Thus, oxygen deficiency, rather than lipid peroxidation by itself, and the essential role of extracellular Ca2+ may be important for CCl4-induced hepatic cell necrosis, in which plasma membrane permeability change may be an early and critical event.

Animals↗
PubMed1975

Pharmacological characterization of cardiac histamine receptors: sensitivity to H1-and H2-receptor agonists and antagonists.

In the isolated guinea pig heart, histamine H1-receptor antagonists inhibit the histamine-induced negative dromotropic effect, but not the positive inotropic and chronotropic effects (Levi and Kuye, 1974, European J. Pharmacol. 27, 330). Burimamide, the H2-receptor antagonist, inhibits the positive chronotropic effect of histamine (Black et al., 1972, Nature 236, 385). In this study, the hypothesis that H1- and H2-receptors selectively mediate the various cardiac effects of histamine was tested: (a) by investigating the inhibition of cardiac histamine effects by burimamide; (b) by studying the cardiac effects of 2-methylhistamine (an H1-agonist) and 4-methylhistamine (an H2-agonist). Burimamide, as a function of concentration, inhibited the positive inotropic and chronotropic effects of histamine, whereas it attenuated the negative dromotropic effect of histamine at the higher concentration only. 4-Methylhistamine caused dose-dependent positive inotropic and chronotropic but not negative dromotropic effects; conversely, with 2-methylhistamine the negative dromotropic effect prevailed. Sinus tachycardia and slowing of atrioventricular conduction were also obtained in the guinea pig in vivo by the i.v. administration of histamine. Burimamide selectively antagonized the positive chronotropic effect, whereas promethazine (an H1-antagonist) selectively inhibited the negative dromotropic effect. These results substantiate the hypothesis that H2-receptors mediate the histamine-induced increase in rate and contractility, whereas H1-receptors mediate the slowing of atrioventricular conduction.

Animals↗
PubMed1980

Antihistamine effect on synaptosomal uptake of serotonin, norepinephrine and dopamine.

The nature and specificity of the effect of histamine H1- and H2-receptor antagonists on the uptake of serotonin (5HT), norepinephrine (NE) and dopamine (DA) were studied in rat forebrain synaptosomes. Low concentrations (0.05-0.50 microM) of the H1-antagonist, pyrilamine, competitively inhibited 5HT uptake (Ki = 0.09 microM), had little effect on NE uptake and no effect on DA uptake. At the same concentrations, two other H1 antihistamines, promethazine and diphenhydramine, and two H2-antihistamines, metiamide and cimetidine, had no effect on 5HT or DA uptake. Diphenhydramine had a small inhibitory effect on NE uptake. It is concluded that at low concentrations, pyrilamine is a relatively selective and potent competitive inhibitor of 5HT uptake, an action which is uncharacteristic of several other antihistamines.

Animals↗
PubMed1982

Bronchodilator and antiallergic effects of thiazinamium chloride in guinea pigs, rats, cats and dogs.

This study characterized the in vivo pulmonary pharmacology of thiazinamium chloride administered largely by the aerosol route in different animal species. The compound has greater anticholinergic but weaker antihistaminic activity than promethazine, the parent compound. It was less potent than atropine or ipratropium as an anticholinergic and had a shorter duration of action, but unlike these compounds it had long-lasting antihistaminic activity. It is effective in both IgG- and IgE-induced models of passive lung anaphylaxis in guinea pigs and rats, respectively. In Ascaris-induced allergic asthma in the conscious dog it produced a dose-related inhibition of the antigen-induced bronchospasm. No major side effects were observed in acute oral and inhalation toxicity studies in guinea pigs or rhesus monkeys. The results demonstrate that thiazinamium chloride is a safe, potent and efficacious bronchodilator after aerosol administration, with a rapid onset and moderate duration of action in animal models.

Anaphylaxis↗
PubMed1987

Evidence for low brain penetration by the H1-receptor antagonist temelastine (SK&F 93944).

Competition by the potent selective H1-receptor antagonist temelastine (SK & F 93944) with [3H]mepyramine binding to mouse cortex H1-receptors has been measured in vitro and vivo. The data were compared with that obtained using the classical H1-receptor antagonists mepyramine and promethazine and indicated that temelastine has relatively low ability to penetrate the blood-brain barrier compared with the latter two compounds. These studies also revealed that temelastine has relatively low affinity for mouse cortex H1-receptors compared with its affinity for H1-receptors in guinea-pig ileum and cortex, suggesting that it may be a useful compound with which to investigate potential H1-receptor tissue and species-related differences.

Animals↗
PubMed1983

Inhibition of lipid peroxidation in spinal cord homogenates by various drugs.

The extent and kinetic profiles of lipid peroxidation induced with Fe2+-ascorbic acid in a homogenate of spinal cord from greyhound dogs were ascertained by measurement of the formation of malondialdehyde (MDA) and chemiluminescence in the presence of four drugs. Changes in MDA and chemiluminescence were correlated as a function of the activator or inhibitors. The kinetic profiles of chemiluminescence which were observed for 25 min after addition of the activator and individual inhibitors were similar regardless of the type of inhibitor studied. The most effective inhibition was by disulfiram which was approximately 11 and 33 times more effective than two other inhibitors, propyl gallate and promethazine, respectively, and 11,000 times more effective than D-alpha-tocopherol.

Animals↗
PubMed1985

Schistosoma mansoni: neurotransmitters and the mobility of cercariae and schistosomules.

The concentration-dependent action of alkyl-isothiouroniums on Schistosoma mansoni cercariae, ranging from partial to total abolition of locomotor and flame cell movements, and/or suppression of virulence, is due to H1-histamine receptor inhibition. Correspondingly, H1-receptor inhibitors of widely different chemical structure, such as clemizol, diphenhydramine, brompheniramine, and promethazine, in 0.03-0.06 nM concentrations, induced an analogous cercarial immobilization reversed by addition of excess histamine. In contrast, the H2-receptor inhibitors cimetidine and metiamide did not immobilize cercariae. Histamine, acetylcholine, and serotonin, added to cercarial suspensions, showed no direct activity. Their participation in the mechanism of cercarial mobility was shown by the dose-dependent effects of antagonists, such as the serotonin antagonist methysergide and the acetylcholinesterase inhibitor physostigmine. These effects were not reversible by addition of serotonin and acetylcholine, respectively. A histamine-irreversible cercarial immobilization induced by the H-liberator 48/80 suggested that, besides H1-receptor inhibition, H-liberation and/or depletion also participated in mobility and survival. The detection of histamine in the cercaria corroborated the participation of histaminergic mechanisms. S. mansoni schistosomules collected from the mouse lung reacted to H1 antihistamines like cercariae, with a dose-dependent reduction of mobility and somatic deformation, such as vacuolization, granulation, and caecal enlargement.

Acetylcholine↗
PubMed1988

Histamine is involved in ethanol-induced jejunal microvascular injury in rabbits.

To examine for the possible involvement of histamine in the jejunal microvascular effects of ethanol, we investigated the effects of (a) intraluminal ethanol on histamine release by the jejunum and (b) simultaneous inhibition of both histamine1 and histamine2 receptors (using promethazine and cimetidine, respectively) on ethanol-induced intestinal plasma protein loss in rabbits. Ethanol increased histamine release by the jejunum both in vivo (p less than 0.01) and in vitro (p less than 0.05). To investigate the effect of antihistamines on ethanol-induced plasma protein loss, we determined the dose of blockers that would completely inhibit the histamine1 and histamine2 receptors. In the absence of antihistamines, ethanol caused a 10-fold increase in jejunal protein loss over the controls (p less than 0.001). Simultaneous inhibition of histamine1 and histamine2 receptors attenuated (p less than 0.025), but did not abolish, the ethanol-induced protein loss. These data are discussed in relation to the literature, and it is concluded that histamine may play a role in the jejunal microvascular effects of ethanol. As the ethanol-induced protein loss was not completely inhibited, other mediators or mechanisms were probably involved.

Animals↗
PubMed1984

Mouse paw anaphylaxis.

Anaphylactic swelling passively transferred to the hind paws of mice with homologous antibodies was investigated. The ascites fluid containing homocytotropic antibodies of the IgG1 class in a high concentration was obtained by repeated injections of bovine serum albumin in complete Freund's adjuvant into the peritoneal cavity of female ICR mice. The standard procedure for mouse paw anaphylaxis defined was as follows: female ICR mice received subcutaneously 25 microliters of a 1:20 diluted ascites in the hind footpad and 2 h later were given intravenously 1.0 mg of the antigen in saline, and subsequently at 5 min intervals paw thickness was assessed by means of a simple thickness gauge. Maximal paw edema occurred invariably 15 min after antigen challenge. Sex difference in response was not observed. Heating at 56 degrees C for 4 h resulted in a reduction of the activity of mouse ascites by approximately 40%. Histological examinations revealed that paw anaphylaxis was accompanied by mast cell degranulation and release of biologically active constituents from mast cell granules. Promethazine, pyrilamine, diphenhydramine, methysergide, cyproheptadine, ketotifen and phenoxybenzamine provided significant protection from the anaphylactic reaction in mice, while bromocriptine, dexamethasone and indomethacin were inactive. Relative drug effectiveness in paw anaphylaxis, passive cutaneous anaphylaxis and active and passive systemic anaphylaxis in mice was compared and discussed. Consequently, it was shown that mouse paw anaphylaxis was not only convenient for quantitative assessment of homocytotropic antibodies, but also useful in the routine work for screening of potential anti-allergic drugs.

Animals↗
PubMed1988

In vitro inhibition of human platelet monoamine oxidase by phenothiazine derivatives.

Nineteen phenothiazines were tested for in vitro inhibition of human platelet type B monoamine oxidase (MAO). The inhibition potency was highly dependent on structures of their side chains. The inhibition was most potent for drugs with (hydroxyethyl-piperazinyl)propyl chains followed in decreasing order by those with (N-methylpiperazinyl)propyl, (2-dimethylamino-2-methyl)ethyl and 3-dimethylaminopropyl chains. Kinetic analyses were carried out for promazine, promethazine, perazine and perphenazine as representatives of each group; the four drugs showed competitive inhibition, and Ki values of 124, 31.4, 19.2 and 22.6 microM, respectively.

Blood Platelets↗
PubMed1986

Surgical exposure induces formation of an arteriovenous permeability gradient for macromolecules in the microcirculation of muscle.

Rous and his colleagues (P. Rous, H. P. Gilding, and F. Smith, 1930, J. Exp. Med. 51, 807-830, F. Smith and P. Rous, 1931, J. Exp. Med. 53, 195-217) uncovered evidence for an arteriovenous gradient of permeability in exchange vessels of muscle. After injecting vital dyes intravenously in laboratory animals, including mice and rats, they examined escape of the dyes from exchange vessels of abdominal muscles, prepared for observation by reflection of the overlying skin. They noted that a particular class of dyes, termed "poorly diffusible," escapes from venules but not from arterioles and capillaries a few minutes after injection. We now assume that the "poor" diffusibility of the dyes stems from their binding to plasma proteins. We repeated similar experiments in mice and rats, using Evans blue as tracer, and also observed leakage of Evans blue from venules but not from other exchange vessels. We made three additional observations. (1) Evans blue leaks from venules only after the skin overlying the abdominal muscles is reflected. (2) Reflection of the skin initiates degranulation of mast cells in the muscles. (3) Leakage of Evans blue from venules is inhibited by administration of promethazine, a histamine and serotonin antagonist, to the animals prior to reflection of the skin. On the basis of our observations, we conclude that the arteriovenous permeability gradient for poorly diffusible dyes in the microcirculation of muscle represents response to tissue injury resulting from reflection of overlying skin.

Abdomen↗
PubMed1988

Enhanced functional responsiveness of the dopaminergic system--the mechanism of anti-immobility effects of antidepressants in the behavioural despair test in the rat.

Imipramine, desipramine, maprotiline and atypical antidepressants such as mianserin, trimipramine and levoprotiline were tested in the behavioural despair test in rats. After chronic treatment (twice daily for 7 days), all the drugs, including trimipramine and levoprotiline, significantly reduced the immobility of rats subjected to forced swimming. Of particular interest are the findings with levoprotiline, which in contrast to other antidepressant drugs did not exert any direct or indirect influence on the metabolism of catecholamines and does not seem to interact with the known receptor systems, except the H1 receptors. However, antihistaminics, such as mepyramine and promethazine (5 and 10 mg/kg i.p.) reduced immobility after single doses but were, in contrast to levoprotiline, inactive after chronic treatment. The anti-immobility effect of levoprotiline, as reported for other antidepressants, appears to be related to enhanced dopaminergic function, since it was antagonised by haloperidol and sulpiride, but not by prazosin. The findings of this study therefore support the assumption that dopaminergic activation is critically involved in the anti-immobility effects of antidepressants. Further, the findings support the predictive value of the test since antidepressant properties of levoprotiline have been observed clinically.

Animals↗
PubMed1985

Organic hydroperoxide-induced lipid peroxidation and cell death in isolated hepatocytes.

Organic hydroperoxides such as tert-butyl hydroperoxide (TBHP) are cytotoxic to suspensions of isolated hepatocytes. The exact mechanism of toxicity is unknown but may involve peroxidation of cellular lipids, alkylation of cellular macromolecules, or alterations in cellular calcium homeostasis. These studies were designed to examine lipid peroxidation as a mechanism of organic hydroperoxide-induced cell death. Hepatocytes isolated from mice were more susceptible to the cytotoxic effects of TBHP than were rat hepatocytes. TBHP-induced cell death was preceded by malondialdehyde formation which was also greater in mouse than rat hepatocytes. Species differences in lipid peroxidation were due to intrinsic properties of hepatocyte membranes as lipids isolated from mouse liver and peroxidized with iron/ascorbate formed approximately eightfold more malondialdehyde than lipids isolated from rat liver. Initiation of lipid peroxidation in mouse and rat hepatocytes with iron/ascorbate caused the formation of malondialdehyde equal to that seen with TBHP and a slight depletion of cellular GSH. As with TBHP, malondialdehyde formation induced by iron/ascorbate was greater in mouse than in rat hepatocytes. However, iron/ascorbate had no effect on hepatocyte viability or morphology from either species. Furthermore, TBHP-induced malondialdehyde and ethane formation in isolated rat hepatocytes were completely blocked by promethazine whereas cell toxicity was altered only slightly. Therefore, these data do not support a role for lipid peroxidation in the acute cytotoxicity of TBHP to suspensions of isolated rat hepatocytes.

Animals↗
PubMed1986

Biochemical mechanisms of cephaloridine nephrotoxicity: time and concentration dependence of peroxidative injury.

These experiments were designed to elucidate the initiating biochemical events mediating cephaloridine (CPH) nephrotoxicity. Renal cortical slices from naive male Fischer-344 rats were incubated at 37 degrees C in a phosphate- or bicarbonate-buffered medium containing 0, 1, 5, or 10 mM CPH. Slices were incubated for 15, 30, 45, 60, 90, 120, and 180 min and evaluated for accumulation of organic ions [p-aminohippurate (PAH) and tetraethylammonium (TEA)], pyruvate-stimulated gluconeogenesis, malondialdehyde (MDA) production, and reduced glutathione (GSH) content. Renal cortical slice accumulation of PAH and TEA was decreased by 5 and 10 mM CPH as early as 120 and 90 min of incubation, respectively. CPH-induced MDA production by renal cortical slices preceded the effects of CPH on organic ion accumulation. Coincubation of CPH with the antioxidants promethazine and N,N'-diphenyl-p-phenylenediamine inhibited CPH-induced lipid peroxidation and changes in organic ion accumulation. In contrast, 5 or 10 mM CPH inhibited gluconeogenic capacity at all time points examined, an effect which was not influenced by antioxidant treatment. Depletion of renal cortical GSH by 5 or 10 mM CPH was evident following 30 min of incubation and was also unaffected by antioxidant treatment. These results support the hypothesis that lipid peroxidation mediates the effects of CPH on renal organic ion transport. The early and profound inhibition of gluconeogenesis by CPH suggests that the biochemical pathways of gluconeogenesis are either proximal to or represent a primary target for CPH nephrotoxicity.

Animals↗
PubMed1983

The effects of single and repeated doses of maprotiline, oxaprotiline and its enantiomers on foot-shock induced fighting in rats.

Foot-shock induced fighting behavior (SIF) in rats was tested after single and repeated dose-treatment (10 mg/kg IP twice daily for 10 days) of maprotiline, oxaprotiline and of (+)- and (-)-enantiomers of oxaprotiline. Marked facilitation of SIF was observed after repeated but not single administration of all drugs including the NA-uptake inactive (-)-enantiomer of oxaprotiline. No enhancement of SIF was seen after multiple dose-treatment with promethazine, an antihistaminic, or atropine. The mechanism of the facilitation of SIF induced by antidepressants maprotiline and oxaprotiline as well as by its enantiomers is unclear. The clear-cut dissociation of the effect of (+)- and (-)-oxaprotiline on the rate of NA-disappearance, but their similar enhancing effect on SIF challenges the assumption of a primary importance of central NA-system in this behavior. By contrast, the increase in jumping behavior recorded additionally to SIF, seems to be a great extent dependent on NA-uptake inhibiting properties of tested drugs.

Aggression↗
PubMed1988

Antihistaminic drugs increase feeding, while histidine suppresses feeding in rats.

The present studies tested the hypothesis that histamine blockade stimulates appetite, while increases in histamine levels suppress appetite. Results show that the classical antihistamines cyproheptadine and promethazine both produced significant and long-lasting increases in food intake. Pronounced appetite stimulation was also seen following the administration of doxepin, the most potent antihistamine among the antidepressants. In contrast, administration of the histamine precursor histidine produced a profound suppression in food intake. The results thus suggest that an inverse relationship may exist between histamine and food intake.

Animal Feed↗
PubMed1991

Stimulation of lipid peroxidation increases the intracellular calcium content of isolated hepatocytes.

Lipid peroxidation induced in isolated rat hepatocytes by FeCl3 (0.1 mM) was associated with an increase in the cytosolic free Ca2+ and in the ionophore-mobilizable Ca2+ content of both mitochondrial and extramitochondrial (endoplasmic reticular) pools. Ca2+ accumulation was completely prevented by the antioxidants promethazine and vitamin E succinate and was not linked to the inhibition of plasma membrane (Ca2+ + Mg2+)-ATPase and Ca2+ transport or to the depletion of intracellular ATP content. Moreover, preincubation of the hepatocytes with the Ca2+ channel blockers verapamil and nifedipine inhibited the elevation of cytosolic Ca2+, as well as the ion accumulation without interfering with the stimulation of lipid peroxidation by iron. These results suggest that peroxidative alterations of the hepatocyte plasma membranes might perturb the functions of verapamil- and nifedipine-sensitive Ca2+ channels resulting in a net influx of Ca2+, which is subsequently sequestrated in the intracellular compartments.

Animals↗
PubMed1984

Critical biochemical functions of isolated hepatocytes as sensitive indicators of chemical toxicity.

Isolated hepatocytes from adult male Wistar rats are a suitable experimental model to study the cytotoxicity of chemicals. Indeed, the isolated cells incubated in suspension in a Waymouth medium supplemented with 10% newborn calf serum maintain critical biochemical functions such as cytochrome P-450-dependent monooxygenase activity, glycogen, and protein synthesis capacities. This cellular model is used to detect the early biochemical effects of various xenobiotics, i.e., chlorpromazine, promethazine, bromobenzene, paracetamol, and isoniazid. Both cellular lysis (measured by the LDH leakage) and metabolic competence of the hepatocytes (glycogen deposits and protein synthesis) are modified as a function of both the duration of exposure to, and the concentration of, the chemicals. These results point out that the evaluation of metabolic functions of isolated cells surviving in suspension might be a sensitive test to predict early cell injury. Indeed, changes in the cellular behavior may occur before or without cell death. Furthermore, since both the cytochrome P-450 content and its dependent monooxygenase activity together with critical biochemical functions of the isolated cells remain stable, this model is of significant interest in ascertaining the mechanisms of toxicity.

Acetaminophen↗