Biomedical subjects

Y Misu

Publications and source records attributed to Y Misu.

At least 73 records · Page 4Linked to original sources

PubMed1994

Role of beta-adrenoceptors in the expression of morphine withdrawal signs.

The effects of intracerebroventricular (i.c.v.) pretreatment with the noradrenergic neurotoxin DSP-4 and beta 1- and beta 2-adrenoceptor antagonists on the expression of morphine withdrawal signs were investigated in mice. Mice were chronically treated with morphine (8-45 mg/kg, s.c.). Several withdrawal signs were observed following naloxone challenge in morphine-dependent mice which had been pretreated with vehicle. Treatment with DSP-4 before the naloxone challenge suppressed the expression of morphine withdrawal signs, including jumping and "wet dog" shakes. Similarly, pretreatment with the beta 1-antagonist atenolol significantly reduced the incidence of naloxone-precipitated jumping and "wet dog" shakes. However, pretreatment with the beta 2-antagonist ICI118,551 suppressed the expression of "wet dog" shakes, but not that of jumping. These findings suggest that the central noradrenergic system may mediate the expression of withdrawal signs. The blocking effects of beta-antagonists indicate that naloxone-precipitated jumping may be mediated predominantly by beta 1-adrenoceptors, while naloxone-precipitated "wet dog" shakes may be mediated by both beta 1- and beta 2-adrenoceptors.

Adrenergic Agents↗

PubMed1994

Evidence for a dopamine receptor subtype sensitive to combination of D1 with D2 antagonist in measurement of G-protein activity using rat striatal membranes.

In rat striatal membranes, various kinds of dopamine receptor agonists stimulated low-Km GTPase activity in a concentration-dependent manner. This stimulation by bromocriptine, pergolide and apomorphine was partially inhibited by sulpiride (SUL), a D2-selective antagonist, markedly inhibited by combination of SUL with SCH 23390 (SCH), a D1-selective antagonist, and not modified by SCH alone. The stimulation by BAM-1110 was resistant to SUL or SCH alone but abolished by combination of SUL with SCH. These findings suggest the presence of another subtype of a dopamine receptor in a functional in vitro bioassay system in rat striata.

Animals↗

PubMed1994

Baroreceptor-aortic nerve-mediated release of endogenous L-3,4-dihydroxyphenylalanine and its tonic depressor function in the nucleus tractus solitarii of rats.

We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter and/or neuromodulator in the central nervous system [Misu Y. and Goshima Y. (1993) Trends pharmac. Sci. 14, 119-123]. This study aimed to explore whether or not endogenous L-DOPA, as a neurotransmitter candidate of the primary baroreceptor afferents, tonically functions to activate depressor neurons in the nucleus tractus solitarii of anesthetized rats. By parallel microdialysis in bilateral nucleus tractus solitarii areas, the basal L-DOPA release was in part inhibited by tetrodotoxin perfusion (1 microM) or Ca2+ deprivation, and was markedly reduced by alpha-methyl-p-tyrosine (200 mg/kg, i.p.), a tyrosine hydroxylase inhibitor. Forty to 100 mM K+ concentration-dependently released L-DOPA. Fifty millimoles K+ repetitively and constantly released L-DOPA. This release was Ca(2+)-dependent. Stimulation of the left aortic nerve (100 Hz, 8 V) repetitively and constantly released L-DOPA and this release was tetrodotoxin-sensitive. Phenylephrine i.v. infused produced L-DOPA release and reflex bradycardia, temporally associated with a rise and subsequent recovery of blood pressure. This release and bradycardia were abolished by denervation of the bilateral carotid sinus and aortic nerves. In addition, L-DOPA methyl ester, a competitive L-DOPA antagonist, when microinjected into depressor sites of the left nucleus tractus solitarii, antagonized depressor responses to mild stimulation (20 Hz, 3 V) of the ipsilateral aortic nerve. This antagonist alone, microinjected bilaterally, elicited a dose-dependent hypertension, which was abolished by alpha-methyl-p-tyrosine. Furthermore, by immunocytochemical analysis seven days after denervation of the left aortic nerve, tyrosine hydroxylase- and L-DOPA-, but not dopamine- and dopamine-beta-hydroxylase-immunoreactivities decreased in the ipsilateral nucleus tractus solitarii and dorsal motor vagus nucleus complex area. In the left ganglion nodosum, denervation decreased staining and number of L-DOPA-immunoreactive cells and staining of tyrosine hydroxylase-immunoreactive cells, but no modification of dopamine-immunoreactive cells was seen. Taken together with previous findings that L-DOPA itself is stereoselectively responsible for cardiovascular control in this nucleus, it is probable that L-DOPA is a neurotransmitter of the primary baroreceptor afferents terminating directly in depressor neurons and/or indirectly in some neurons within a microcircuit, including depressor neurons of the nucleus tractus solitarii. Endogenously released L-DOPA itself tonically functions to activate depressor neurons for regulation of blood pressure in the rat nucleus tractus solitarii.

Animals↗

PubMed1993

Evidence for L-dopa relevant to modulation of sympathetic activity in the rostral ventrolateral medulla of rats.

By microdialysis in the rostral ventrolateral medulla (RVLM) of anesthetized rats, the spontaneous L-3,4-dihydroxyphenylalanine (DOPA) release was partially Ca(2+)-dependent and tetrodotoxin-sensitive and was markedly reduced by alpha-methyl-p-tyrosine (alpha-MPT; 200 mg/kg, i.p.). K+ (50 mM) Ca(2+)-dependently evoked L-DOPA. By microinjections into unilateral RVLM, L-DOPA (30-300 ng) produced dose-dependent hypertension and tachycardia similarly in rats untreated, treated with i.p. 3-hydroxybenzylhydrazine, a central DOPA decarboxylase inhibitor, or with i.v.t. 6-hydroxydopamine. These responses were antagonized by L-DOPA methyl ester (1.5 micrograms), a competitive L-DOPA antagonist. D-DOPA, dopamine, noradrenaline or adrenaline (300 ng) produced no effect. Furthermore, L-DOPA methyl ester alone microinjected into bilateral RVLM (2 micrograms x 2) produced prolonged hypotension and bradycardia, which were abolished by alpha-MPT. These data suggest that L-DOPA is relevant to modulation of sympathetic activity in the rat RVLM.

Animals↗

PubMed1993

Delta opioid receptor mediates phospholipase C activation via Gi in Xenopus oocytes.

Cloned mouse delta-subtype opioid receptor (DOR1) was expressed in Xenopus oocytes to study the signal transduction. Opioid delta-agonists evoked a calcium-dependent chloride current in oocytes injected with mRNA derived from DOR1, together with that from the alpha subunit of Gi1. The delta-agonist-induced current was blocked by naltrindol, a delta-specific antagonist. The delta-agonist evoked no or very weak currents in oocytes with the alpha subunit of Gq or G(o). These findings indicate the functional coupling between the opioid delta-receptor and phospholipase C through an activation of Gi.

Analgesics↗

PubMed1993

Transmitter-like L-3,4-dihydroxyphenylalanine tonically functions to mediate vasodepressor control in the caudal ventrolateral medulla of rats.

By microdialysis in the unilateral caudal ventrolateral medulla (CVLM) of anesthetized rats, the spontaneous L-3,4-dihydroxyphenylalanine (L-DOPA) release was in part tetrodotoxin-sensitive or Ca(2+)-dependent and was abolished by i.p. alpha-methyl-p-tyrosine (alpha-MPT), a tyrosine hydroxylase inhibitor. High K+ (50 mM) Ca(2+)-dependently evoked L-DOPA. By unilateral microinjections into the CVLM, L-DOPA (10-100 ng) produced dose-dependent, marked hypotension and bradycardia similarly in rats untreated, treated with i.p. 3-hydroxybenzylhydrazine, a central DOPA decarboxylase inhibitor, or with i.v.t. 6-hydroxydopamine. These responses were antagonized by L-DOPA methyl ester, a competitive L-DOPA antagonist. A depressor response to dopamine or noradrenaline (100 ng) was far smaller and slower in onset than that to L-DOPA (30 ng). D-DOPA (100 ng) produced no effect. Furthermore, L-DOPA methyl ester microinjected into bilateral CVLM produced some hypertension and tachycardia, which were markedly reduced by alpha-MPT. Transmitter-like L-DOPA tonically functions to mediate vasodepressor control in CVLM of rats.

Animals↗

PubMed1993

L-dopa induces Ca(2+)-dependent and tetrodotoxin-sensitive release of endogenous glutamate from rat striatal slices.

L-DOPA (10-1000 microM) concentration-dependently released glutamate (Glu) from superfused rat striatal slices. D-DOPA and dopamine (300 microM) produced no effects. The L-DOPA-induced release of Glu was not affected by 3-hydroxybenzylhydrazine (20 microM), an L-aromatic amino acid decarboxylase inhibitor. L-DOPA methyl ester (200 microM), a selective L-DOPA antagonist, antagonized the effect of L-DOPA in a competitive manner. Ca2+ deprivation and tetrodotoxin decreased L-DOPA (300 microM)-induced release of Glu. These findings indicate that L-DOPA induces a transmitter-like release of Glu via activation of a recognition site for itself.

Animals↗

PubMed1993

Is L-dopa an endogenous neurotransmitter?

Since the 1960s, L-3,4-dihydroxyphenylalanine (L-dopa), a precursor of dopamine, has been thought to occur in the cytoplasm of catecholaminergic neurones. L-Dopa is traditionally believed to be an inert amino acid that exerts actions and effectiveness in Parkinson's disease via its conversion to dopamine by L-aromatic amino acid decarboxylase. In contrast to this generally accepted idea, Yoshimi Misu and Yoshio Goshima propose, in this Viewpoint article, that L-dopa itself is an endogenous neurotransmitter or neuromodulator in the CNS. This hypothesis is mainly based on the findings that L-dopa is released in a transmitter-like manner and that exogenously applied levodopa produces some responses.

Animals↗

PubMed1993

Endogenously released DOPA is probably relevant to nicotine-induced increases in locomotor activities of rats.

The relevance of endogenously released DOPA to the (+/-)-nicotine-induced increase in locomotor activities was explored in rats. This increase was dose (0.1-1.0 mg/kg, s.c.)-dependent, stereo-selective and mecamylamine (1.0 mg/kg, s.c.)-sensitive, but was not antagonized by L-dopa methyl ester (200 micrograms, i.v.t.), a competitive L-dopa antagonist. Then, by microdialysis, low doses of alpha-methyl-p-tyrosine (alpha-MPT, i.p.) at 1-10 mg/kg, were tested to find a dose that selectively inhibits the basal DOPA release in the striata: the release was consistently inhibited by 3 mg/kg without any tendency to inhibit the basal dopamine release. Pretreatment with this dose did inhibit the nicotine-induced increases in locomotor activities. This suggests that endogeneously released DOPA is in part relevant to the nicotine-induced behavior in rats.

Animals↗

PubMed1993

L-dopa potentiates presynaptic inhibitory alpha 2-adrenoceptor- but not facilitatory angiotensin II receptor-mediated modulation of noradrenaline release from rat hypothalamic slices.

L-dopa is a potentiator for presynaptic beta-adrenoceptors. We studied whether L-dopa potentiates the activities of other presynaptic receptors to modulate the evoked noradrenaline (NA) release in rat hypothalamic slices. UK14304 (0.1-1 microM), a selective alpha 2-agonist, concentration-dependently inhibited NA release. Noneffective 10 pM L-dopa potentiated the UK14304-induced inhibition. This potentiation was selectively antagonized by 1 nM L-dopa methyl ester, a competitive L-dopa antagonist, while yohimbine antagonized both the inhibition by UK14304 alone and its potentiation by L-dopa. However, 10 pM L-dopa produced no effect on angiotensin II (0.1-1 nM)-induced facilitation. L-dopa potentiates activities of presynaptic beta- and alpha 2-adrenoceptors but not those of angiotensin II receptors on rat hypothalamic NA neurons.

Adrenergic alpha-Agonists↗

PubMed1993

Review on the relationship between nicotinic acetylcholine receptors and dopaminergic neurotransmission in the central nervous system--dopa is an endogenous neuroactive substance.

L-3,4-Dihydroxyphenylalanine (DOPA) is believed to be an inert precursor for dopamine (DA). Contrary, transmitter-like endogenous DOPA is released from in vitro and in vivo striata: DOPA is released by neuronal activities under physiological conditions from striata of conscious rats. Furthermore, exogenous nanomolar DOPA itself produces an in vitro presynaptic response to facilitate the catecholamine release. An in vivo postsynaptic depressor response is elicited by DOPA microinjected into the nucleus tractus solitarii. These responses are antagonized by L-DOPA methyl ester, a competitive DOPA antagonist. In striata, DOPA is an endogenous potentiator for presynaptic beta-adrenoceptors to facilitate the DA release and also probably for postsynaptic D2-receptors to increase locomotor activities. Nicotine releases DA and transmitter-like DOPA in vitro and in vivo striata. Nicotine (0.1-1.0 mg/kg, sc) dose-dependently increases locomotor activities. This increase is stereoselective and mecamylamine (1.0 mg/kg, sc)-sensitive but not antagonized by L-DOPA methyl ester (200 micrograms, ivt). Then, a selective low ip dose of alpha-methyl-p-tyrosine (alpha-MPT) to inhibit the basal release of DOPA without decreasing the basal release of DA was explored in vivo striata: it was 3 mg/kg. Pretreatment with this dose did inhibit the nicotine-induced increases in locomotor activities. This result suggests that endogenously released DOPA is in part relevant to nicotine-induced behavior in rats.

Animals↗

PubMed1992

Transmitter-like 3,4-dihydroxyphenylalanine is tonically released by nicotine in striata of conscious rats.

Microdialysis and high performance liquid chromatography with an electrochemical detector were applied to compare the characteristics of nicotine-evoked release of endogenous 3,4-dihydroxyphenylalanine (DOPA) from striata of conscious rats and those of the release of dopamine (DA). Dialysates were collected every 20 min 3-8 h after the start of perfusion. Nicotine was perfused for 20 min through a probe. (+/-)-Nicotine (100-300 microM) constantly and repeatedly released DOPA and DA over a similar time course in a dose-dependent manner. The ratio of the DOPA and DA release evoked was approximately 1:3. The (+/-)-nicotine (200 microM)-induced DOPA release was mecamylamine (500 microM)-sensitive, tetrodotoxin (100 nM)-sensitive and Ca2+ (removal plus 12.5 mM Mg2+ addition)-dependent. The (+)-isomer produced no DOPA release. These characteristics of DOPA release were almost the same as those of DA release. Furthermore, mecamylamine alone inhibited the basal release of DOPA but not of DA. Nicotine released stereoselectively endogenous DOPA via nicotinic acetylcholine receptors from striata of freely moving rats in a manner similar to transmitter DA. These acetylcholine receptors function tonically for the release of DOPA. These findings are further support for our proposal that DOPA is an endogenous neuroactive substance.

Animals↗

PubMed1992

Evidence for L-dopa systems responsible for cardiovascular control in the nucleus tractus solitarii of the rat.

Microinjections of L-DOPA (10-100 ng) into the medial area of the nucleus tractus solitarii (NTS) led to dose-dependent decreases in arterial blood pressure and heart rate in rats treated with i.p. 3-hydroxybenzylhydrazine, a central inhibitor of DOPA decarboxylase, or similarly with intraventricular 6-hydroxydopamine. D-DOPA, dopamine or noradrenaline (100 ng) produced no effect. L-DOPA methyl ester (1 microgram), a competitive antagonist for L-DOPA, microinjected into NTS, blocked the depressor and bradycardic responses to L-DOPA. High K+ (40 mM) released endogenous DOPA in a Ca(2+)-dependent manner from slices of the rat dorsomedial medulla including NTS. These results support the hypothesis that there exist systems of L-DOPA itself responsible for cardiovascular regulation in NTS of rats. This regulatory action of L-DOPA seems to be postsynaptic in nature.

Animals↗

PubMed1992

Transmitter-like basal and K(+)-evoked release of 3,4-dihydroxyphenylalanine from the striatum in conscious rats studied by microdialysis.

Using microdialysis and HPLC, characteristics of the release of endogenous 3,4-dihydroxyphenylalanine (DOPA) from striatum in conscious rats were studied in comparison with those of 3,4-dihydroxyphenylethylamine (dopamine; DA). Purified L-aromatic amino acid decarboxylase (AADC) converted a putative peak of DOPA to DA. The retention time of DOPA differed from that of DA and major metabolites of DA and norepinephrine. The DOPA peak of dialysates comigrated with that of authentic DOPA when the pH of the HPLC buffer was modified. The ratio of the basal release of DOPA:DA was 1:2. 3-Hydroxybenzylhydrazine (NSD-1015; 100 mg/kg, i.p.), an AADC inhibitor, markedly increased the basal release of DOPA but produced no effect on DA. The basal release of DOPA was markedly decreased by alpha-methyl-p-tyrosine (200 mg/kg, i.p.), substantially tetrodotoxin (1 microM) sensitive, and Ca2+ (removal plus 12.5 mM Mg2+ addition) dependent. Fifty millimolar K+ released DOPA and this release was also Ca2+ dependent. These characteristics of the basal and evoked release of DOPA were similar to those of DA. The ratio of the evoked release of DOPA:DA was 1:3. These results indicate that DOPA is released under physiological conditions and by K(+)-induced depolarization in a manner similar to that for transmitter DA from striatum in freely moving rats.

Animals↗

PubMed1992

L-dopa-like regulatory actions of L-threo-3,4-dihydroxyphenylserine on the release of endogenous noradrenaline via presynaptic receptors in rat hypothalamic slices.

Effects of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) on the spontaneous release and the stimulus(2 Hz)-evoked release of endogenous noradrenaline were studied in rat hypothalamic slices with functioning L-aromatic amino acid decarboxylase (AADC) and with AADC inhibition. In non-inhibited slices, spontaneous release was not modified by L-threo-DOPS at 1 pM-100 nM, tended to increase at 1-10 microM and increased at 100 microM. Noradrenaline tissue content slightly increased at 100 microM. Stimulated release was concentration-dependently facilitated at 1-1000 pM and tended to decrease gradually from a maximum at 10 nM-10 microM. Under AADC inhibition, spontaneous release concentration-dependently increased at 10-100 microM by 60% of the increase seen in slices without AADC inhibition. Increase in noradrenaline tissue content was abolished. L-threo-DOPS produced a triphasic pattern on stimulated release; concentration-dependent facilitation at 1-1000 pM similar to that seen in slices with functional AADC, no facilitation at 10-1000 nM, and a concentration-dependent increment at 10-100 microM. The facilitation at 1 nM was stereoselective and was antagonized by (-)-propranolol 10 nM, and no facilitation at 100 nM was restored to the maximum by yohimbine 10 nM, DG-5128 10 nM or S-sulpiride 1 nM. Furthermore, L-threo-DOPS (1-1000 pM)-induced facilitation was competitively antagonized by L-dopa methyl ester, a competitive antagonist for L-dopa, with a pA2 value of 13.6, whereas it was noncompetitively antagonized by (-)-propranolol.

Animals↗

PubMed1992

Effects of nanomolar to submillimolar carteolol on noradrenaline release in the absence and presence of uptake1 and uptake2 blockers in guinea pig pulmonary arteries.

Effects of nanomolar to submillimolar carteolol, a non-selective beta-antagonist, on the evoked release at 1 Hz and the spontaneous release in the absence and presence of uptake1 and uptake2 blockers were studied in pulmonary arteries, isolated from guinea pigs, and then preloaded with [3H]noradrenaline. dl-Carteolol at 10(-8), 10(-7) and 10(-6) M applied at the increasing concentrations inhibited the evoked [3H]-release in untreated arteries and in desipramine and corticosterone-treated arteries. The spontaneous [3H]-release slightly but significantly increased or tended to increase in untreated arteries. dl-Carteolol at 10(-5) and 10(-4) M clearly and concentration-dependently increased the spontaneous [3H]-release in untreated and cocaine-treated arteries. This increase was markedly inhibited by further pretreatment with normetanephrine. The evoked [3H]-release was not altered by dl-carteolol at 10(-5) M, but increased at 10(-4) M. This increase was not modified by cocaine and by cocaine and normetanephrine. d-Carteolol at 10(-5) and 10(-4) M produced effects similar to those of dl-carteolol. Nanomolar to micromolar dl-carteolol inhibits the evoked [3H]-release, which supports our previous conclusion that this inhibition is due to blockade of tonically functioning presynaptic beta 2-adrenoceptors. Carteolol at the higher concentrations seems to become a substrate for an uptake2 mechanism and to produce an unknown sympathomimetic activity in guinea pig pulmonary arteries.

Animals↗

PubMed1991

Picomolar concentrations of L-dopa stereoselectively potentiate activities of presynaptic beta-adrenoceptors to facilitate the release of endogenous noradrenaline from rat hypothalamic slices.

Interactions between (-)-isoproterenol and DOPA on the release of endogenous noradrenaline (NA) evoked by electrical field stimulation (2 Hz, alternative polarity) were studied in rat superfused hypothalamic slices in the presence of 3-hydroxybenzylhydrazine, an inhibitor of L-aromatic amino acid decarboxylase, and cocaine. Isoproterenol (0.3-3 nM) facilitated the NA release in a concentration-dependent manner, while 10 pM L-DOPA alone produced no effect. This facilitation at 0.3-3 nM was potentiated by 20-70% by simultaneously applied 10 pM L-DOPA but that at 3 nM was not modified by 10 pM D-DOPA. This potentiation of the isoproterenol (3 nM)-induced facilitation of the NA release was concentration-dependent at 1-10 pM of L-DOPA. L-DOPA methyl ester (1 nM) antagonized the L-DOPA (10 pM)-induced potentiation of the facilitation of the NA release by 3 nM isoproterenol to a level of the facilitation by isoproterenol alone, whereas 10 nM (-) propranolol antagonized both the facilitation by isoproterenol alone and its potentiation by L-DOPA to a control level. Picomolar concentrations of L-DOPA stereoselectively act on a recognition site for itself, and then potentiate activities of presynaptic beta-adrenoceptors to facilitate the NA release from rat hypothalamic slices.

Animals↗

PubMed1991

Ipsilateral but not contralateral blockade of excitatory amino acid receptors in the caudal ventrolateral medulla inhibits aortic baroreceptor reflex in rats.

The caudal ventrolateral medulla (CVLM) contains vasodepressor neurons which, when activated, decrease vasomotor tone. To investigate whether excitatory amino acid receptors in the CVLM of the rat are involved in mediation of the aortic baroreceptor reflex, we microinjected amino acid antagonists unilaterally into the CVLM and examined their effects on the depressor response to electrical stimulation of the aortic nerve which contains mainly baroreceptor afferent fibers in rats. Male Wistar rats were anaesthetized with urethane, paralyzed and artificially ventilated. To block reflex vagal effects, methylatropine (1 mg/kg) was given intravenously. Kynurenate (227 ng), an excitatory amino acid antagonist, injected ipsilaterally but not contralaterally into the CVLM markedly inhibited the depressor response to aortic nerve stimulation, while both injections produced a similar small increase in basal blood pressure. Muscimol (1 ng), a GABA receptor agonist, injected ipsilaterally into the CVLM partly inhibited the baroreflex response, while it produced a moderate increase in basal blood pressure. 2-Amino-5-phosphonovalerate (APV) (10 ng), a N-methyl-D-aspartate (NMDA) receptor antagonist, and MK-801 (30 ng), a NMDA receptor channel blocker, partly inhibited the baroreflex response. MK-801 (30 ng) injected into the CVLM reduced the depressor response to the NMDA receptor agonist NMDA (0.3 ng) but not to the quisqualate receptor agonist quisqualate (0.1 ng) and the kainate receptor agonist kainate (0.1 ng), while kynurenate (227 ng) inhibited the depressor response to all three excitatory amino acid receptor agonists. These findings provide further evidence for the presence of excitatory amino acid receptors involved in mediating the aortic baroreceptor reflex in the rat CVLM.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗