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PubMed1982

The antihypertensive effect of U-0521 (3',4'-dihydroxy-2-methylpropiophenone).

The synthetic catechol, U-0521, (3',4'-dihydroxy-2-methylpropiophenone) is a competitive inhibitor of both tyrosine hydroxylase and catechol-O-methyltransferase. Continuous subcutaneous administration of 10 mumoles per day of U-0521 via Alzet osmotic minipumps to adult male Spontaneously Hypertensive Rats (SHR) reduced blood pressure from 160 mmHg to 125 mmHg. This effect occurred within two days, persisted for the two weeks that the pumps were in place, and reversed gradually upon cessation of U-0521 administration. Similar treatment of U-0521 to normotensive Wistar Kyoto rats (WKY) did not result in a similar hypotentensive effect. Subcutaneous administration of the same dose to juvenile SHRs led to a blockade in the expression of hypertension. After the five week treatment period, the blood pressure of the U-0521 treated animals escalated rapidly to match the saline treated controls. The antihypertensive effect of U-0521 on SHRs also occurred when the compound was delivered by the oral route at the rate of 50 mg/kg/day.

Aging↗
PubMed1982

The lack of effect of bupropion HCL (Wellbatrin) on the secretion of growth hormone and prolactin in humans.

The effect of bupropion HCL (Wellbatrin), a new anti-depressant, on the secretion of GH and PRL in healthy male subjects and male hyperprolactinaemic patients was studied. The study was a randomised double-blind test in which 6 subjects and 6 patients who had been treated with neuroleptics were each, in accordance with the random plan, treated once with placebo and once with 200 mg bupropion p.o.. After administration of the test substance, blood was drawn to measure bupropion, GH and PRL up to 240 minutes thereafter. Neither in the healthy men nor in the patients could a specific effect of bupropion on the secretion of GH be shown in comparison to placebo although bupropion in all subjects and patients was well reabsorbed. As opposed to the results of Stern et al. (5), no change in the secretion of PRL was measured in either the healthy subjects or the hyperprolactinaemic patients. In addition, no change in the TRH-induced stimulation of PRL could be measured. The results of the present study offer no positive contribution towards an explanation of the mechanism of bupropion.

Antipsychotic Agents↗
PubMed1983

Localization of rat striatal monoamine oxidase activities towards dopamine, serotonin and kynuramine by gradient centrifugation and nigro-striatal lesions.

Subfractionation of the crude synaptosomal-mitochondrial fraction of rat striatum in a continuous sucrose gradient in a zonal rotor led to the following results. The distribution pattern of monoamine oxidase (MAO) activity towards dopamine (DA) was very similar to the pattern of MAO activity towards serotonin (5HT), but differed from the pattern of MAO activity towards kynuramine (KYN). As 5HT is specifically deaminated by MAO-A while KYN is a common MAO substrate, this supports earlier suggestions that in rat striatal preparations DA is deaminated preferentially by MAO-A. The patterns of the MAO activities towards DA and 5HT were clearly dissimilar, despite considerable overlap, to the patterns of tyrosine hydroxylase (TH) and DOPA decarboxylase (DD) activity, both marking the presence of striatal dopaminergic synaptosomes. The peak activities were separated and all patterns were symmetrical without showing a shoulder. This indicates that rat striatal MAO activity towards DA and 5HT is not specifically or for the greater part localized in dopaminergic terminals. We also investigated the effects of electrolytic and 6-hydroxydopamine lesions of the substantia nigra, both causing extensive degeneration of striatal dopaminergic terminals as appeared from the large decrease of striatal TH and DD activity. However, neither type of lesion induced a reduction of the MAO activity towards any of the substrates used. It is concluded that the amount of MAO activity towards DA and 5HT (probably MAO-A activity) present in dopaminergic terminals is very low compared with the total activity of this enzyme in rat striatal tissue.

Animals↗
PubMed1984

Cardiac norepinephrine releasing action of kynuramine, an endogenous diamine derived from L-tryptophan.

Kynuramine, an endogenous metabolite of L-tryptophan, was found to function as an indirectly acting sympathomimetic amine in rat atria in vitro. Kynuramine released tritium from atria preloaded with [3H]norepinephrine (NE), an effect which was blocked completely by pretreatment with reserpine or 6-hydroxydopamine. Release by kynuramine was calcium-independent and was potentiated by inhibition of monoamine oxidase but was only partially sensitive (50%) to inhibition by cocaine (10(-4)M). The ability of kynuramine to enter cardiac cells was demonstrated in whole atria by measuring its intracellular deamination rate by monoamine oxidase. Blockade of neuronal uptake (cocaine) and extraneuronal uptake (SKF 550) had no effect upon this measure. It is concluded that knyuramine releases cardiac NE, in part, by a cocaine-sensitive mechanism but that the process operating for the membrane transport of kynuramine in both neuronal and non-neuronal cells remains uncertain. The data are discussed in relation to the possible cardiac consequences of L-tryptophan ingestion in man.

Animals↗
PubMed1985

The conditioned place preference paradigm in rats: effect of bupropion.

The effect of bupropion in the conditioned place preference paradigm in rats is described. In doses between 10 and 50 mg/kg i.p. bupropion increased the time rats spent in a shuttle box compartment conditioned to this compound. This effect of bupropion was not blocked by pretreatment of the animals with 0.1 mg/kg i.p. haloperidol or 50 mg/kg i.p. sulpiride. The same doses of the neuroleptics did, however, attenuate locomotor hyperactivity induced by bupropion. Bupropion thus seems to belong to the group of CNS stimulants whose effect in the conditioned place preference paradigm is not blocked by neuroleptics.

Animals↗
PubMed1987

Inhibition of 15-hydroxy prostaglandin dehydrogenase and increase of prostaglandin E2: effect of sofalcone on rat gastric mucosa.

The effect of sofalcone, an anti-ulcer agent, on gastric mucosal prostaglandin (PG) metabolism was studied. Gastric mucosal PGE2 was determined in rats in which PGE2 synthesis was inhibited by preadministration of indomethacin. Oral administration of sofalcone at doses of 200 and 400 mg/kg significantly inhibited the PG metabolizing enzyme, 15-hydroxy-PG-dehydrogenase (15-OH-PG-DH) activity and increased PGE2 contents in the rat gastric mucosa. The inhibition of 15-OH-PG-DH activity was accompanied by an increase of PGE2 contents up to 6 hours after the administration of sofalcone. These changes, however, were not observed 12 hours after its administration. Intraperitoneally administered sofalcone also inhibited 15-OH-PG-DH activity and increased PGE2 content. The inhibition of 15-OH-PG-DH activity by sofalcone was noncompetitive and uncompetitive against substrates NAD and PGE1, respectively. These results suggest that the increase of the gastric PGE2 level is mainly due to the inhibition of 15-OH-PG-DH activity, and this increase in PGE2 may be involved in the anti-ulcer effect of sofalcone.

Animals↗
PubMed1990

High affinity dopamine reuptake inhibitors as potential cocaine antagonists: a strategy for drug development.

The addictive and euphorogenic effects of cocaine are thought to result primarily from inhibition of dopamine reuptake. Although the potency of cocaine-like drugs as inhibitors of DA reuptake is highly correlated with their potency as reinforcers in animals, several potent DA reuptake blockers (bupropion, nomifensine, benztropine, and mazindol) have not been reported to produce addiction or euphoria in humans. Based on these observations in humans, DA reuptake inhibitors are classified into two groups; type 1 blockers, which produce addiction and euphoria, and type 2 blockers, which do not. Given that type 1 and type 2 blockers act at the same site (the DA transporter), the author suggests that type 2 agents may antagonize the effects of cocaine, and might prove useful in the treatment of cocaine addiction.

Benztropine↗
PubMed1983

Daily bupropion injections for 3 weeks attenuate the NE stimulation of adenylate cyclase and the number of beta-adrenergic recognition sites in rat frontal cortex.

In rats receiving daily doses (50 mg/kg i.p. twice daily) of bupropion HCI (WellbutrinR) repeated for 21 days the Bmax of the beta-adrenergic receptor recognition sites located in the frontal cortex is reduced. This decrease is not associated with a decrease of the apparent affinity of these recognition sites. However the Vmax of the cAMP (cyclic AMP) generating system stimulated by NE is reduced suggesting that similarly to other antidepressants bupropion down regulates beta-adrenergic receptors located in the frontal cortex. Bupropion neither inhibits MAO (monoamine oxidase) nor releases biogenic amines but only weakly inhibits monoamine uptake in vitro.

Adenylyl Cyclases↗
PubMed1983

Bupropion: a new antidepressant drug, the mechanism of action of which is not associated with down-regulation of postsynaptic beta-adrenergic, serotonergic (5-HT2), alpha 2-adrenergic, imipramine and dopaminergic receptors in brain.

The present experiments were undertaken to determine: (1) whether bupropion had any direct effects on receptors present in rat brain; (2) whether the drug could down-regulate postsynaptic beta-adrenergic, alpha 2-adrenergic, serotonergic, imipramine and dopaminergic receptors after chronic administration, as had been demonstrated for tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, electroconvulsive therapy (ECT) and "atypical" antidepressants. Bupropion was found to be weak or inactive when its affinity for 14 different receptors present in brain was assessed by binding assays. The drug failed to desensitize beta-adrenergic receptors in the cerebral cortex of the rat as determined by [3H]dihydroalprenolol binding, after being administered at 25 mg/kg (i.p.) once a day for 6 weeks, or after being administered by the intraperitoneal route to rats at doses as large as 150 mg/kg per day for 4 days. When administered at doses of 37.5, 75 and 150 mg/kg per day for 21 days, the drug had no effect on beta-adrenergic, alpha 2-adrenergic, imipramine or serotonergic (5-HT2) receptors in the brain of the rat as determined by Scatchard analysis of the binding data. These data show that the antidepressant activity of bupropion is not associated with a down-regulation of receptors in the CNS commonly implicated in the mechanism of action of antidepressant drugs. Bupropion also produced a dose-dependent tendency to decrease the activity of norepinephrine-stimulated adenylate cyclase in slices of cerebral cortex obtained from rats treated chronically with the drug. However, the decrease was highly variable, was most obvious in tissues obtained from rats receiving large, non-pharmacologically relevant doses (150 mg/kg per day) of the drug and was statistically significant at only one of three concentrations of the agonist that produced maximal stimulation of the enzyme.

Adenylyl Cyclases↗
PubMed1986

Effect of plasma from patients containing bupropion and its metabolites on the uptake of norepinephrine.

The uptake of norepinephrine into cortical punches from the brain of the rat was studied in the presence of buffer and plasma from patients containing bupropion and its metabolites. Even though bupropion and its metabolite (compound II) were equipotent in inhibiting the uptake of NE in buffer, compound II was twice as active as bupropion in the presence of human plasma. When the inhibition of uptake of NE in the presence of plasma, obtained from patients on bupropion on steady-state, was correlated with levels of bupropion and its metabolites (II, III, IV) a highly significant correlation was seen in the presence of compound II. Since this compound accumulated in plasma from patients 20-100 times that of the parent compound, the mode of action of bupropion may in part be due to the effect of this compound on the uptake of NE.

Animals↗
PubMed1989

Effects of tizanidine, eperisone and afloqualone on feline dorsal horn neuronal responses to peripheral cutaneous noxious and innocuous stimuli.

The effects of eperisone and afloqualone have been compared with those of tizanidine on excitatory responses of spinal dorsal horn neurones, evoked by noxious and innocuous peripheral stimuli. Tizanidine, administered intravenously or iontophoretically, resulted in a profound, long-lasting and selective depression of the responses to noxious stimuli. In contrast, intravenous injection of eperisone produced either a rapidly reversible depression of responses to both noxious and innocuous stimuli or had no effect on these responses. Iontophoretic administration of eperisone also reduced neuronal responses to both forms of peripheral stimuli and that induced by quisqualate. This depressant action of eperisone was rapidly reversible but was often accompanied by a reduction of the amplitude of the action potentials. Afloqualone had no depressant action on any evoked response when administered iontophoretically. However, intravenous injection of this agent resulted in weak depressant effects on responses to noxious, innocuous or both types of stimuli, of a few of the neurones tested. This effect of afloqualone was not dose-dependent and was mimicked by control injections of the vehicle in which it was suspended. It is suggested that the muscle relaxants, eperisone and afloqualone, in contrast to tizanidine, do not possess any direct spinal antinociceptive activity.

Air↗
PubMed1989

Dissociation of the actions of uptake blockers upon dopamine overflow and uptake in the rat nucleus accumbens: in vivo voltammetric data.

Fast cyclic voltammetry, at carbon fibre microelectrodes, was used to monitor stimulated overflow and uptake of DA in the nucleus accumbens of the rat. Several recognised blockers of neuronal uptake of DA were examined for their actions on each process. Benztropine, cocaine, GBR 12909 and nomifensine elevated the overflow of DA, while only nomifensine and bupropion blocked uptake. The actions of the drugs upon uptake did not correlate with their effects on overflow of DA. It is therefore concluded that the mechanisms by which the drugs influence overflow and uptake are different. It cannot be assumed that the elevation of extracellular DA is solely the result of blockade of uptake by these drugs.

Animals↗
PubMed1982

Taste responses to neohesperidin dihydrochalcone in rats and baboon monkeys.

Preference-aversion behavior to solutions containing neohesperidin dihydrochalcone (NHDHC) was studied rats and baboon monkeys. Electrophysiological responses evoked by application of NHDHC solutions to taste receptors innervated by the chorda tympani and the glossopharyngeal nerves were also measured. As a group, rats were indifferent to solutions containing up to 1.2 x 10(-3) M NHDHC in short and long-term preference tests. A solution containing the very high concentration of 8.2 x 10(-3) M NHDHC was consumed less than water by all rats. The aversive behavior of rats to the 8.2 x 10(-3) M NHDHC solution appeared to be due to taste quality rather than olfaction. When percent preferences were calculated on an individual basis for the long-term preference tests, 59% of the rats were indifferent to solutions containing up to 1.2 x 10(-3) M NHDHC, 33% of the animals found this solution aversive and less than 8% showed preference. Behavioral responses to a solution of 3.4 x 10(-4) M aspartame also varied considerably among rats. The electrophysiological data were in line with the behavioral responses suggesting weak taste responses for NHDHC in rats. More pronounced responses observed in the glossopharyngeal nerve as compared to the chorda tympani. Baboon monkeys showed a strong preference for solutions containing 1.6 x 10(-5) M-1.6 x 10(-3) M NHDHC. A solution of 1.6 x 10(-2) M was consumed to a lesser extent than water. It is concluded that baboon monkeys present a better experimental model than rats for investigating the sweetness of NHDHC.

Analysis of Variance↗
PubMed1984

Antivirus agent, Ro 09-0410, binds to rhinovirus specifically and stabilizes the virus conformation.

The antiviral mechanisms of Ro 09-0410 (4'-ethoxy-2'-hydroxy-4,6'-dimethoxychalcone), which inactivates rhinovirus exclusively, have been investigated. It was suggested that Ro 09-0410 bound to human rhinovirus type 2 (HRV-2) and made it inactive, since the reduced infectivity was completely restored to original levels by extraction of the agent with chloroform [H. Ishitsuka, Y. Ninomiya, C. Ohsawa, M. Fujiu, and Y. Suhara (1982) Antimicrob. Agents Chemother. 22, 617-621]. This was confirmed using radioactively labeled Ro 09-0410 and HRV-2. HRV-2 was inactive while bound to the agent, whereas a subline of HRV-2 resistant to the agent had no binding site for the agent. Ro 09-0410 appeared to bind to some specific site(s) on the virion of susceptible virus strains. Treatment of rhinovirus at pH 5 or 56 degrees caused a change of the virion size and greatly reduced its infectivity. Ro 09-0410 could no longer bind to HRV-2 after such treatment. On the other hand, when the virion bound with Ro 09-0410 was treated at pH 5 or 56 degrees, the Ro 09-0410 remained bound and the conformational alteration of the virion did not take place. Furthermore, Ro 09-0410 protected HRV-2 from the reduction of infectivity caused by mild acid or heat treatment, as revealed by infectivity measurements after extraction of the agent with chloroform. These results suggest that Ro 09-0410 binds to the HRV-2 virion and prevents viral replication in the cell.

Antiviral Agents↗