The effect of dextran sulfate on the survival time and mitochondrial function of adriamycin (ADM)-treated mice was studied. ADM-induced toxicity in mice was reduced by treatment with dextran sulfate (60, 100, 300, and 600 mg/kg, sc). The optimum dextran sulfate dose for protection against ADM-induced toxicity in mice was about 200 mg/kg/day (sc) and 100 mg/kg/day (po). Groups treated with dextran sulfate (300 mg/kg) had significantly improved mitochondrial function as measured by oxygen uptake of state 3 (p less than 0.01), dinitrophenol-altered respiration (p less than 0.01), and respiratory control index level (p less than 0.01). From these observations, it was concluded that ADM-induced toxicity due to reduced mitochondrial function can be ameliorated by the membrane stabilizing effect of dextran sulfate.

Administration, Oral↗

PubMed1985

Effects of iminodibenzyl antipsychotic drugs on cerebral dopamine and alpha-adrenergic receptors.

The iminodibenzyl antipsychotic drugs, clocapramine, carpipramine and Y-516 were studied in order to elucidate their mechanisms of action. They all accelerated the accumulation of the dopamine (DA) metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC), in the striatum and nucleus accumbens of the rat brain. Only Y-516 antagonized in vivo the apomorphine-induced inhibition of DA synthesis as estimated from the accumulation of 3,4-dihydroxyphenylalanine (DOPA) in the decarboxylase-inhibited rat striatum after cessation of nerve impulse flow. All three drugs showed high affinity for DA receptors labelled by [3H]haloperidol and [3H]ADTN in the rat striatum in vitro, with the order of potency Y-516 greater than clocapramine greater than carpipramine. All accelerated the accumulation of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), in mouse brain. They showed high affinity for alpha 1-adrenoceptors labelled by [3H]WB 4101 and for alpha 2-adrenoceptors labelled by [3H]clonidine in the rat cerebral cortex in vitro. Although they all had the same level of affinity for the alpha 1-adrenoceptors, Y-516 had less affinity for the alpha 2-adrenoceptors than did clocapramine and carpipramine. The above results indicate that these drugs are potent DA antagonists which block alpha 1- and alpha 2-adrenoceptors in the brain.

Animals↗

PubMed1985

Modification of the antiepileptic actions of phenobarbital and phenytoin by the taurine transport inhibitor, guanidinoethane sulfonate.

We investigated whether chronic administration of guanidinoethane sulfonate, an inhibitor of taurine uptake, could modify the antiepileptic actions of phenobarbital and phenytoin on maximal electroshock seizures in mice. Treatment with 1% guanidinoethane sulfonate decreased the taurine concentration in the brain to 76% of the control value. Under these conditions, neither the severity of tonic convulsions of maximal electroshock seizures nor the threshold for tonic extension caused by electroshock was altered. However, treatment with guanidinoethane sulfonate lessened the antiepileptic actions of phenobarbital and phenytoin on electroshock seizures. The brain concentrations of phenobarbital and phenytoin were unaltered by administration of guanidinoethane sulfonate. The brain concentrations of guanidinoethane sulfonate and total guanidino compounds were unchanged by the injection of either phenobarbital or phenytoin. It is suggested that the observed loss of anticonvulsive potency of phenobarbital and phenytoin may have been related to the decrease in taurine concentration produced by guanidinoethane sulfonate.

Amino Acids↗

PubMed1985

Tissue distribution of acetaldehyde in rats following acetaldehyde inhalation and intragastric ethanol administration.

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Acetaldehyde↗

PubMed1985

Effect of indomethacin, tiaprofenic acid and dicrofenac on rat gastric mucosal damage and content of prostacyclin and prostaglandin E2.

Gastric ulcerogenicity and depletion of endogenous prostaglandins (PGs) content induced by tiaprofenic acid, dicrofenac and indomethacin were examined using the same antiinflammatory effective doses. Male Wistar rats were given each of these drugs intragastrically 24, 18, and 3 hrs before sacrifice in the following doses (mg/kg): indomethacin (0.8, 4 and 20); tiaprofenic acid (1.2, 6 and 30); dicrofenac (0.8, 4 and 20). Endogenous prostacyclin (PGI2) and PGE2 in fundic mucosa were determined by radioimmunoassay. The three compounds produced fundic mucosal lesions in a dose-dependent manner. However, tiaprofenic acid and dicrofenac were both less potent than indomethacin in producing gastric mucosal lesions at similar antiinflammatory doses. Mucosal PGE2 content was abolished by the three compounds in the following doses (mg/kg): indomethacin (4 and 20); tiaprofenic acid (6 and 30); dicrofenac (20). Mucosal PGI2 was maintained around 50% of the control value in rats given tiaprofenic acid in a dose of 6 mg/kg or dicrofenac in a dose of 4 mg/kg, while indomethacin in a dose of 4 mg/kg markedly reduced mucosal PGI2 to 17% of the control value. In larger doses, tiaprofenic acid and dicrofenac were also significantly less potent in reducing mucosal PGI2 than indomethacin. These results suggest that the difference in ulcerogenicity between indomethacin and the other two compounds was closely related to their potency in decreasing PGI2 in the gastric (fundic) mucosa.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Role of the sympathetic nerve in bladder and urethral sphincter function during the micturition cycle in the dog evaluated by pressure flow EMG study.

The role of the sympathetic nerve on bladder and urethral sphincter function during the whole micturition cycle, including the collecting and emptying phases, was evaluated on 10 decerebrated dogs by pressure flow EMG study. A series of experiments was performed before and after hypogastric nerve transection. In the control condition and after hypogastric nerve transection, reflex micturition with bladder contraction and spasmodic rhythmic sphincter contractions occurred. Urodynamic parameters of the micturition cycle were statistically compared between control and nerve transection experiments. Threshold volume, threshold pressure and opening pressure showed a small but significant change after nerve transection. A decrease in voided volume seems to be secondarily accompanied with a decrease in threshold volume. It seems that adrenergic nerves play a certain role in bladder function during the collecting phase of the micturition cycle.

Animals↗

PubMed1985

Effects of the autonomic antagonists on canine urethral responses to autonomic nerve stimulation.

The effects of the autonomic antagonists on urethral activity was studied in female dogs. Urethral responses produced by autonomic nerve stimulation were measured with pressure and motility changes in control conditions and after administration of autonomic antagonists. Phentolamine and guanethidine reduced both hypogastric and pelvic nerve mediated responses. It seems that urethral smooth muscle function is greatly influenced by adrenergic drugs.

Animals↗

PubMed1985

Effects of autonomic agonists on in vivo female canine urethral motility.

The response of the urethra to intra-arterially administered autonomic agonists was studied in vivo by measuring the motility and pressure changes in female dogs. Phenylephrine produced shortening along the transverse axis with an increase in urethral pressure in a dose-dependent manner. Isoproterenol produced lengthening along the transverse axis with a decrease in urethral pressure. Both acetylcholine and dimethylphenylpiperazinium did not produce consistent patterns in urethral response. It seems that adrenergic drugs act predominantly on the circular muscle layer and cholinergic drugs act equally on both the circular and longitudinal muscle layers.

Acetylcholine↗

PubMed1985

Increased numbers of hypodense eosinophils in the blood of patients with bronchial asthma.

We investigated the density of blood eosinophils from patients with asthma using polyvinylpyrrolidone-coated silica gel (Percoll) discontinuous density gradient centrifugation of peripheral blood leukocytes. Ten patients with allergic asthma, 10 normal subjects, and 2 patients with the hypereosinophilic syndrome (HES) were studied. The density distribution profiles of eosinophils from normal subjects showed: (1) peaks at densities of 1.085 to 1.090 g/ml and (2) inflection points or nadirs near 1.082 g/ml, below which only 10% of eosinophils were found. On the basis of these results, we divided eosinophils into 2 subpopulations: normodense (greater than 1.082 g/ml) and hypodense (less than 1.082 g/ml). Densities of eosinophils from patients with asthma and HES peaked at 1.083 and 1.076 g/ml (mean values), respectively, significantly lighter than eosinophils from normal donors (p less than 0.005 and p less than 0.001, respectively). The proportions of hypodense eosinophils in patients with asthma and HES were 35 and 95%, respectively, and were significantly greater than that in normal donors (p less than 0.002 and p less than 0.001, respectively). The density distribution profiles of a normal subject were stable over time, but those of asthmatic patients varied with time. For the 22 participants, there was a positive correlation between log-transformed blood eosinophil counts and the percentage of hypodense eosinophils (r = +0.86, p less than 0.001). Similarly, for 15 of them, plasma eosinophil granule major basic protein correlated with the numbers of peripheral blood eosinophils (r = +0.92, p less than 0.0005) and hypodense eosinophils (r = +0.92, p less than 0.0005). Thus, a portion of the eosinophils in asthmatic patients and most of the eosinophils in patients with HES are hypodense.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1985

A sustained increase of microsomal heme oxygenase activity following treatment of rats with Bacillus Calmette-Guerin and Corynebacterium parvum: its possible relation to the decrease of cytochrome P-450 content.

The alterations of various enzymes responsible for drug metabolism and heme metabolism were examined in the liver of female rats treated with Bacillus Calmette-Guerin (BCG) and Corynebacterium parvum (CP). Hepatic drug metabolizing enzyme activities and microsomal cytochrome P-450 and b5 content were significantly decreased for up to 15 and 10 d by a single i.v. administration of BCG and CP, respectively. In contrast, microsomal heme oxygenase activity was markedly increased after BCG and CP treatment and the increased enzyme activity was sustained in parallel with the decrease of drug metabolizing enzymes. Both BCG and CP also caused a significant decrease of delta-aminolevulinic acid synthetase activity shortly after their administrations. The decreased enzyme activity returned to normal levels by 12 h after the treatment of rats with BCG and CP. In addition, hepatosplenomegaly was observed in BCG and CP treated rats. Dose related changes of these microsomal enzymes were seen following the administration of BCG and CP. Additionally, there were sex differences in the effects of BCG and CP on the alteration of microsomal enzymes, female rats being more sensitive than male rats. These results suggest that the decrease of cytochrome P-450 and b5 content and drug metabolizing enzyme activities by BCG and CP could be related, at least in part, to the prolonged increase of heme oxygenase activity, that may lead to the increased breakdown of heme available for the synthesis of these hemoproteins.

5-Aminolevulinate Synthetase↗

PubMed1985

[Synthesis of anthraquinones using directed lithiation reaction].

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Antibiotics, Antineoplastic↗

PubMed1985

[Neuroleptic properties of Y-516, a new iminodibenzyl derivative].

Iminodibenzyl derivatives have been prepared in our laboratories for development as psychotropic drugs. Among them, carpipramine and clocapramine have already been introduced for clinical use as neuroleptic drugs. In the present study, the pharmacological properties of Y-516, a new iminodibenzyl derivative, were compared with those of carpipramine, clocapramine, haloperidol and sulpiride. Y-516 inhibited apomorphine (0.5 mg/kg, s.c.)-induced hyperactivity in mice, apomorphine (10 mg/kg, s.c.)-induced hypothermia in mice, apomorphine (0.1 mg/kg, s.c.)-induced vomiting in dogs, methamphetamine (2 mg/kg, s.c.)-induced hyperactivity in mice and methamphetamine (50 mg/kg, i.p.)-induced mortality in grouped mice. Y-516 also suppressed both lateral hypothalamic self-stimulation behavior in rats and circling behavior induced by methamphetamine (5 mg/kg, i.p.) in rats with unilateral 6-hydroxydopamine lesions of the striatum. In these tests, Y-516 was 2--3 times more potent than clocapramine, but less potent than haloperidol. The inhibitory effect of Y-516 on apomorphine (1.25 mg/kg, i.v.)-induced gnawing behavior in rats was slightly more potent than that of clocapramine. Y-516 in combination treatment with methamphetamine (5 mg/kg, i.p.) did not induce mortality in rats; however, carpipramine and sulpiride did. The cataleptogenic action of Y-516 was almost equipotent to that of clocapramine. From these results, Y-516 possesses a post-synaptic dopamine receptor blocking action similar to that of the iminodibenzyl antipsychotic drugs, suggesting its potential usefulness as an antipsychotic drug.

Animals↗

PubMed1985

Effects of cholinergic drugs on aversive operant behavior induced by dorsal central gray stimulation in rats.

Involvement of a central cholinergic mechanism in the central aversive operant behavior induced by dorsal central gray (DCG) stimulation was investigated in rats. Each animal was chronically implanted with bipolar electrodes at the DCG and was trained to press a lever to decrease the DCG-stimulation current. Physostigmine (0.1 and 0.2 mg/kg, i.p.) and arecholine (0.5-2.0 mg/kg, i.p.) produced an increase of DCG-stimulation threshold at 0.5-2 hr and 1-4 hr, respectively, after the administration. On the other hand, scopolamine (0.1-0.5 mg/kg, i.p.) and atropine (5 and 10 mg/kg, i.p.) caused a marked decrease of the threshold at 0.5-2 hr after. In addition, an increasing effect of physostigmine on the threshold was decreased by scopolamine. Physostigmine potentiated the increasing effect of chlorimipramine on the stimulation threshold, while scopolamine suppressed it. These results suggest that the operant behavior induced by DCG-stimulation may be related to not only the central serotonergic mechanism but also to the cholinergic mechanism.

Animals↗