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Biomedical subjects

S Z Langer

Publications and source records attributed to S Z Langer.

At least 145 records · Page 8Linked to original sources
PubMed1985

Interaction between tricyclic and nontricyclic 5-hydroxytryptamine uptake inhibitors and the presynaptic 5-hydroxytryptamine inhibitory autoreceptors in the rat hypothalamus.

In slices of the rat hypothalamus prelabeled with [3H]-5-hydroxytryptamine [( 3H]-5-HT), exposure to lysergic acid diethylamide or 5-methoxytryptamine decreased, in a concentration-dependent manner, the release of 3H-transmitter elicited by electrical stimulation. These inhibitory effects were antagonized by the 5-HT receptor antagonist methiothepin (1 microM). Exposure to methiothepin on its own increased in a concentration-dependent manner the electrically evoked overflow of [3H]-5-HT. Exposure to tricyclic antidepressants, like imipramine and amitriptyline, and to nontricyclic 5-HT uptake inhibitors, like paroxetine and citalopram, did not modify by themselves the electrically evoked overflow of [3H]-5-HT. Yet, the four inhibitors of neuronal uptake of 5-HT, antagonized the inhibition by lysergic acid diethylamide or 5-methoxytryptamine of the electrically induced release of [3H]-5-HT. After depletion of endogenous stores of 5-HT by pretreatment with para-chlorophenylalanine (300 mg/kg i.p.), the inhibitors of 5-HT uptake increased the electrically evoked release of [3H]-5-HT in a concentration-dependent manner. Their order of potency to enhance 5-HT overflow after pretreatment with parachlorophenylalanine paralleled their potency at inhibiting neuronal uptake of 5-HT (paroxetine = citalopram greater than imipramine greater than amitriptyline). In para-chlorophenylalanine-treated rat hypothalamic slices, these inhibitors of 5-HT uptake antagonized the inhibition by 5-HT autoreceptor agonists of the electrically evoked release of [3H]-5-HT to a similar extent than was observed in control rats. It is concluded that inhibition of 5-HT uptake reduces the effectiveness of 5-HT autoreceptor agonists to inhibit the electrically evoked release of [3H]-5-HT, irrespective of the chemical structure of the uptake inhibitor or of the levels of endogenous 5-HT achieved in the synaptic gap.

5-Methoxytryptamine↗
PubMed1985

Inhibition by 5,6-dihydroxy-2-dimethylaminotetralin (M7) of noradrenergic neurotransmission in the rabbit hypothalamus: role of alpha-2 adrenoceptors and of dopamine receptors.

Rabbit hypothalamic slices were prelabeled with [3H]norepinephrine and transmitter release elicited by electrical stimulation. In the presence of 10 microM cocaine and in a low Ca++ medium (0.65 mM), exposure for 8 min to exogenous dopamine (0.01-1 microM) inhibited, in a concentration-dependent manner, the electrically evoked release of [3H]norepinephrine. This inhibitory effect of dopamine on [3H]norepinephrine release was antagonized by the dopamine receptor antagonist S-sulpiride (1 microM), but remained unchanged in the presence of the alpha-2 adrenoceptor antagonists idazoxan (1 microM) or yohimbine (0.1 microM). These results indicate that, in a low Ca++ medium, exposure to dopamine decreased [3H]norepinephrine overflow in rabbit hypothalamic slices through the exclusive activation of presynaptic inhibitory dopamine receptors. M7 (5,6-dihydroxy-2-dimethylaminotetralin) is a potent agonist at central presynaptic dopamine autoreceptors and at peripheral alpha-2 adrenoceptors. Exposure to M7 in a normal Ca++ medium, inhibited in a concentration-dependent manner the electrically evoked release of [3H]norepinephrine without affecting the spontaneous outflow of radioactivity. The slope of the concentration-effect curve for these inhibitory effects of M7 was rather flat and the maximal inhibition obtained was 80%. The selective D2 receptor antagonist S-sulpiride (1 microM) failed to produce a significant shift to the right in the concentration-effect curve for the inhibitory effects of M7 on [3H]norepinephrine release. The preferential alpha-2 adrenoceptor antagonist yohimbine (0.1 microM) significantly antagonized the inhibition of [3H]norepinephrine release elicited by 0.01 microM M7, but not for higher concentrations of this aminotetraline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

5-methoxytryptoline and close analogs as candidates for the endogenous ligand of the 3H-imipramine recognition site.

3H-Imipramine labels with high affinity a site associated with the macromolecular complex of the serotonin transporter in brain and platelets. There is a good correlation between the potencies of drugs at inhibiting 3H-5HT uptake and at inhibiting 3H-imipramine binding. Dissociation experiments indicate that the site labelled by 3H-imipramine is not identical with the substrate recognition site of the serotonin transporter and thus, it appears that 3H-imipramine labels a modulatory site for the 5HT transport system. On this basis, the existence of an endacoid acting on the 3H-imipramine recognition site to modulate 5HT uptake is discussed. The possibility that 5-methoxytryptoline or a closely related analog may be the endogenous ligand for the 3H-imipramine recognition site is analysed on the basis of the fact that 5-methoxytryptoline is a potent inhibitor of 3H-imipramine binding that also inhibits 3H-5HT uptake.

Binding, Competitive↗
PubMed1985

Trace amines inhibit the electrically evoked release of [3H]acetylcholine from slices of rat striatum in the presence of pargyline: similarities between beta-phenylethylamine and amphetamine.

Amphetamine (AMPH) inhibits the electrically evoked release of [3H]acetylcholine (ACh) from rat striatal slices through the activation of inhibitory dopamine receptors. Naturally occurring analogs of amphetamine (AMPH) such as beta-phenylethylamine (beta-PEA), tyramine (TYR) and octopamine (OCT) are present in trace amounts in the brain of several species. We have studied in this model, in comparison with AMPH, the effects of beta-PEA, TYR and OCT, in order to explore if their central effects are mediated through an action involving dopaminergic nerve terminals or whether they activate a specific receptor directly. In contrast to the results obtained with AMPH, in the absence of inhibition of monoamine oxidase activity, the three amines beta-PEA (0.1-10 microM), TYR (0.1-10 microM) and OCT (10 microM) did not affect the electrically evoked release of [3H]ACh. On the other hand, in the presence of pargyline (10 microM), the three amines inhibited the electrically evoked release of [3H]ACh and all subsequent experiments were carried out in the presence of pargyline. After pretreatment with reserpine (5 mg/kg s.c., 24 h), which results in a 95% depletion of the endogenous dopamine content, OCT lost its inhibitory effect on [3H]ACh release, whereas beta-PEA and TYR still inhibited the electrically evoked release of [3H]ACh. Reserpine pretreatment (5 mg/kg s.c., 24 h) combined with alpha-methyl-p-tyrosine (300 mg/kg i.p., 2 h) reduced endogenous dopamine levels by 99.9%, but, under these conditions, beta-PEA, TYR and AMPH still retained their inhibitory effect on [3H]ACh, release. These inhibitory effects of beta-PEA and AMPH on [3H] ACh release were antagonized by S-sulpiride (0.1 microM). In striatal slices from untreated rats, the inhibition of [3H]ACh released by beta-PEA (30 microM), TYR (30 microM) or AMPH (10 microM) was abolished completely after a 6-hydroxydopamine lesion of the nigro-striatal dopaminergic system. The present data indicate that in order to inhibit the release of [3H]ACh from rat striatal slices in vitro, OCT requires the integrity of vesicular stores of dopamine. On the other hand, beta-PEA, TYR and AMPH are still active when the dopamine levels are depleted, although they require the integrity of the dopaminergic nerve terminal. Inhibition of monoamine oxidase is essential to demonstrate the inhibitory effects of exogenous beta-PEA, TYR and OCT on cholinergic transmission. Our results indicate that a hypothesis concerning a possible physiopathological role of endogenous beta-PEA or TYR should involve concomitant changes in monoamine oxidase activity.

Acetylcholine↗
PubMed1984

[3H]Imipramine binding and [3H]5HT uptake in human blood platelets: changes after one week chlorimipramine treatment.

In platelets of normal volunteers taking chlorimipramine (50 mg/day) for one week, the saturable uptake of [3H]5HT was fully inhibited at day 8, but returned to control values at day 15. The Bmax of [3H]imipramine binding was decreased by 65% at day 8 and remained significantly below control values at day 15. If the present findings can be extrapolated to other antidepressants, the reported decreases in [3H]imipramine binding in depression may partly reflect residual treatment effects. It cannot be excluded that, in depression, the platelet [3H]imipramine receptor already is down-regulated maximally which would preclude a further down-regulation due to antidepressant drug therapy.

Adult↗
PubMed1984

5HT-receptor antagonist properties of SCH 23390 in vascular smooth muscle and brain.

The dopamine D1-receptor antagonist SCH 23390 was a potent competitive antagonist of 5HT-induced vasoconstriction in the isolated perfused rat tail artery preparation (pA2 8.17) but a very weak antagonist of phenylephrine-induced responses (pA2 5.94). In rat brain cerebral cortex, SCH 23390 inhibited 5-HT2-sensitive [3H]spiperone binding with an IC50 of 112 nM. Binding of [3H]5HT to 5HT1 receptors in the cortex was inhibited by SCH 23390 with an IC50 of 2.49 microM. SCH 23390 has significant affinity for 5HT receptors in addition to the reported selective dopamine D1-receptor antagonist properties.

Animals↗
PubMed1984

Reduced Vmax of 3H-serotonin uptake but unchanged 3H-imipramine binding in the platelets of untreated hypertensive subjects.

The uptake of 3H-serotonin, endogenous serotonin content and 3H-imipramine binding were measured in platelets of subjects with essential hypertension and matched control volunteers. The uptake of 3H-serotonin and endogenous serotonin levels in platelets were significantly reduced while 3H-imipramine binding did not differ in the two experimental groups. These results provide further evidence that the uptake site for serotonin and the binding site for 3H-imipramine although associated, may be modified independently.

Biological Transport↗
PubMed1984

Saturable uptake of [3H]-tryptamine in rabbit platelets is inhibited by 5-hydroxytryptamine uptake blockers.

[3H]-tryptamine is taken up by rabbit platelets through an active and saturable process which is temperature sensitive, sodium-dependent and inhibited by imipramine and non-tricyclic 5-hydroxytryptamine (5-HT) uptake blockers. There is an excellent correlation between the Ki for the inhibition of [3H]-tryptamine and [3H]-5-HT uptake in rabbit platelets for a series of 5-HT uptake blockers. These results indicate that [3H]-tryptamine is actively transported through the membrane of blood platelets by the same carrier that transports 5-HT.

Animals↗
PubMed1984

Differential effects of the stereoisomers of 3PPP on dopaminergic and cholinergic neurotransmission in superfused slices of the corpus striatum.

The two enantiomers of 3PPP were tested on the spontaneous and electrically-evoked release of 3H-dopamine from slices of the rabbit caudate nucleus and of 3H-acetylcholine (3H-ACh) from slices of the rat caudate nucleus. In caudate slices labelled with 3H-dopamine, exposure to (+)3PPP (0.1-1 microM) facilitated the spontaneous outflow of radioactivity with a concomitant inhibition of the electrically-evoked release of 3H-dopamine. In the presence of cocaine 10 microM, exposure to (+)3PPP (1 microM) inhibited the electrically evoked release of 3H-dopamine without modifying the spontaneous outflow of radioactivity. This inhibitory effect was not significantly antagonized by S-sulpiride 0.01 microM. Exposure to (+)3PPP 1 microM inhibited the electrically-evoked release of 3H-ACh, and this effect was not modified by pretreatment with reserpine alone, or in combination with alpha-methyl-p-tyrosine (alpha-MT). In contrast to the (+) enantiomer, exposure to (-)3PPP (0.1-1 microM) facilitated the electrically-evoked release of 3H-dopamine without affecting the spontaneous outflow of radioactivity. (-)3PPP antagonized the inhibitory effect of apomorphine on the electrically-evoked release of 3H-dopamine. Exposure to (-)3PPP 1 microM did not modify the spontaneous or the electrically-evoked release of 3H-ACh. Yet, this concentration of (-)3PPP antagonized significantly the inhibitory effect of 0.03 microM apomorphine, 1 microM d-amphetamine, and 1 microM (+)3PPP on the electrically-evoked release of 3H-ACh (-)3PPP (0.1-1 microM) was about 100 times less potent than S-sulpiride at antagonizing the inhibitory effect of apomorphine on the electrically-evoked release of 3H-ACh.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1984

Alpha-adrenoreceptor subtypes in blood vessels: physiology and pharmacology.

A significant advance in the field of neurotransmission was made with the discovery of presynaptic release-modulating alpha-adrenoreceptors on noradrenergic nerve terminals. The concept of presynaptic modulation of noradrenaline release developed in parallel with the pharmacological evidence for two subtypes of alpha-adrenoreceptors as defined by a different profile of affinity and relative order of potencies for agonists and for antagonists. The alpha 1-adrenoreceptor is stimulated preferentially by methoxamine and cirazoline and blocked selectively by prazosin or corynanthine. The alpha 2-adrenoreceptor is stimulated preferentially by agonists such as clonidine, TL-99, GHT-933, and UK-14,304, and the responses mediated by these agonists are selectively blocked by the alpha 2-adrenoreceptor antagonist idazoxan. In blood vessels, both the alpha 1- and the alpha 2-adrenoreceptor subtypes are present postsynaptically, where they mediate vasoconstriction, although the alpha 1-adrenoreceptor is the predominant receptor in vascular smooth muscle. Presynaptically on noradrenergic nerve terminals, the stimulation of inhibitory alpha 2-adrenoreceptors reduces the depolarization-evoked release of the transmitter. In most vascular beds, the alpha 1-adrenoreceptor is also the preferentially innervated subtype. In spontaneously hypertensive rats, smooth-muscle alpha 2-adrenoreceptors mediate vasoconstrictor responses to exogenous noradrenaline and to sympathetic nerve stimulation to a greater extent than in the corresponding normotensive Wystar-Kyoto rats, which may point to a pathophysiological role of these alpha 2-adrenoreceptors in hypertension.

Adrenergic alpha-Agonists↗
PubMed1984

Heterogeneity of smooth muscle alpha adrenoceptors in rat tail artery in vitro.

Vascular smooth muscle alpha adrenoceptors in the proximal end of the rat isolated tail artery have been classified by determining pA2 values and -log KB values for the antagonists prazosin, corynanthine and idazoxan (RX 781094, a new synthetic alpha-2 adrenoceptor antagonist) against norepinephrine. The effects of the antagonists on responses to intramural sympathetic nerve stimulation were also assessed. Artery segments were perfused and superfused with Krebs' solution containing cocaine (4 microM) and propranolol (1 microM). Maximum responses to KCl, norepinephrine and nerve stimulation were not significantly different from one another. Corynanthine (0.1-100 microM), prazosin (10 nM-1 microM) and idazoxan (1-100 microM) caused competitive antagonism of norepinephrine responses with pA2 values consistent with the presence of alpha-1 adrenoceptors. However, idazoxan (10-100 nM) also caused parallel shifts in the concentration-response curves to norepinephrine with -log KB values higher than those consistent with the presence of alpha-1 adrenoceptors. The results have been interpreted to suggest a predominance of smooth muscle alpha-1 adrenoceptors in addition to a subpopulation of smooth muscle alpha-2 adrenoceptors which also contribute to vasoconstrictor responses to norepinephrine. In contrast to the results obtained with exogenous norepinephrine, responses to electrical stimulation were exquisitely sensitive to blockade by prazosin but resistant to idazoxan , suggesting an involvement of an alpha-1 adrenoceptor in these responses. It is concluded that idazoxan may be used to distinguish alpha-1 and alpha-2 adrenoceptors on vascular smooth muscle in vitro and that the results favor the existence of alpha-1 and alpha-2 adrenoceptors in terms of the existing subclassification scheme for alpha adrenoceptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1984

Smooth muscle alpha-2 adrenoceptors mediate vasoconstrictor responses to exogenous norepinephrine and to sympathetic stimulation to a greater extent in spontaneously hypertensive than in Wistar Kyoto rat tail arteries.

The alpha adrenoceptor-mediated vasoconstriction in isolated perfused tail arteries from spontaneously hypertensive (SHR) and age matched Wistar Kyoto (WKY) normotensive rats has been examined. Responses induced by periarterial field stimulation, exogenous norepinephrine or the selective alpha-1 adrenoceptor agonist methoxamine were preferentially antagonized by prazosin in both SHR or WKY tail arteries. However, in SHR only, the alpha-2 adrenoceptor antagonist idazoxan (RX 781094) at low concentrations, significantly antagonized responses to periarterial field stimulation and to exogenous norepinephrine. Except at rather high concentrations, idazoxan was inactive as an antagonist of responses induced by methoxamine. The alpha-1 adrenoceptor blocking agent prazosin was a very potent antagonist of the responses induced by periarterial field stimulation and by methoxamine. These results indicate that alpha-2 adrenoceptors predominate in both SHR and WKY tail arteries, but a significant subpopulation of smooth muscle alpha-2 adrenoceptors is present in tail arteries of SHR but not of WKY rats. In contrast to WKY normotensive rats, postjunctional alpha-2 adrenoceptors may also be involved in the vasoconstrictor responses to sympathetic nerve stimulation in tail arteries of SHR.

Adrenergic alpha-Antagonists↗
PubMed1984

Evidence that exogenous but not endogenous norepinephrine activates the presynaptic alpha-2 adrenoceptors on serotonergic nerve endings in the rat hypothalamus.

In superfused rat hypothalamic slices, clonidine, norepinephrine (NE) and 6-fluoronorepinephrine reduced the electrically evoked release of recently taken up [3H]-5-hydroxytryptamine (5-HT). The inhibitory action of these drugs involves the activation of presynaptic alpha-2 adrenoceptors and it was antagonized by the alpha adrenoceptor antagonists phentolamine or RX 781094. In contrast to the facilitating effect of alpha-2 adrenoceptor antagonists on the electrically evoked [3H]NE overflow in rabbit hypothalamic slices, neither phentolamine nor RX 781094 modified the stimulation-evoked release of [3H]-5-HT at concentrations which completely antagonized the inhibitory action of NE, 6-fluoronorepinephrine and clonidine on 5-HT neurotransmission. In the presence of cocaine, which inhibits the neuronal uptake of NE and increases the concentration of this neurotransmitter in the synaptic gap, alpha-2 adrenoceptor antagonists were still unable to modify the electrically evoked release of [3H]-5-HT. It is concluded that presynaptic alpha-2 adrenoceptors present on serotonergic nerve endings in the hypothalamus are not activated by endogenous NE and do not seem to play a physiological role in the regulation of serotonergic neurotransmission. However, presynaptic inhibitory alpha-2 adrenoceptors can be acted upon by exogenous agonists to inhibit 5-HT release. On the other hand, the presynaptic alpha-2 adrenoceptors on noradrenergic nerve terminals in the rabbit and rat hypothalamus are acted upon by released NE because the alpha-2 adrenoceptor antagonists by themselves increase the electrically evoked release of [3H]NE.

Animals↗
PubMed1983

Antagonism by tetrahydro-beta-carboline of the vasoconstrictor responses to tryptamine in rat tail arteries.

Tryptamine and 5-HT mediate vasoconstriction in the isolated perfused rat tail artery. These agonists were differentiated by the classical serotonin receptor antagonists methysergide and ketanserin which were significantly more potent against 5-HT-induced responses. Neither prazosin nor RX 781094 alone or in combination reduced the vasoconstriction produced by tryptamine. Tetrahydro-beta-carboline (THBC) was devoid of agonist properties and behaved as a competitive antagonist of tryptamine but not of 5-HT. THBC also had alpha-adrenoceptor blocking properties in this preparation.

Adrenergic alpha-Agonists↗