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S Z Langer

Publications and source records attributed to S Z Langer.

At least 163 records · Page 9Linked to original sources
PubMed1983

[3H]imipramine binding in subcellular fractions of rat cerebral cortex after chemical lesion of serotonergic neurons.

The specific high affinity binding of [3H]imipramine was investigated in subcellular fractions of rat cerebral cortex before and after chemical denervation of serotonergic neurons. In control animals the proportion of the total number of [3H]imipramine binding sites in the nuclear (N), heavy mitochondrial (M), light mitochondrial (L) and microsomal (P) fractions corresponded respectively to 3, 45, 16 and 36% of the total number of binding sites. After chemical lesion of serotonergic neurons with 5,7-dihydroxytryptamine (5,7-DHT) the density of [3H]imipramine binding sites in fractions M and L was decreased by 42 and 52% respectively. In these experiments the uptake of [3H]5-HT in fractions M and L decreased by approximately 80%. The Bmax of [3H]imipramine binding in fraction P was decreased by 80% after chemical denervation with 5,7-DHT. In the control group there was no detectable [3H]5-HT uptake while the endogenous serotonin levels in fraction P were rather low. Our results support the view that the high affinity binding of [3H]imipramine is partly located on serotonergic nerve terminals. The significance of the [3H]imipramine binding sites present in the microsomal (P) fraction remains to be clarified.

5,7-Dihydroxytryptamine↗
PubMed1983

[3H]RX 781094: a new antagonist ligand labels alpha 2-adrenoceptors in the rat brain cortex.

[3H]RX 781094 [(imidazolinyl-2)-2 benzodioxane-1,4 [3H]chlorhydrate], a specific alpha 2-adrenoceptor antagonist radioligand, has been used to characterize alpha 2-adrenoceptors in rat cortical membranes. [3H]RX 781094 binding is reversible, saturable and stereospecific. It labels with high affinity a single population of non-interacting sites. The KD value was 3.9 +/- 0.4 nM and the Bmax 189.0 +/- 12.4 fmol/mg protein. Competition curves with different alpha-adrenoceptor agonists and antagonists showed that the binding sites labelled with [3H]RX 781094 had the pharmacological characteristics of alpha 2-adrenoceptors. Pretreatment with reserpine (2.5 mg/kg s.c., 24 h before the experiment) did not affect the KD or Bmax values of [3H]RX 781094 binding. Chemical destruction of noradrenergic pathways by systemic injection of DSP4 or intracerebral injection of 6-hydroxydopamine did not modify the KD or the Bmax of [3H]RX 781094 binding. It is concluded that the major proportion of alpha 2-adrenoceptors labelled with [3H]RX 781094 are not localised to noradrenergic nerve terminals.

Adrenergic alpha-Antagonists↗
PubMed1983

Specific high affinity [3H]imipramine binding sites in rat lung are associated with a non-neuronal uptake site for serotonin.

[3H]Imipramine binds to rat lung membranes. The binding is saturable, of high affinity and sodium-dependent. Drug displacement studies indicate that the binding site in rat lung is similar to that already described in the brain cortex. Tricyclic antidepressants inhibited [3H]imipramine binding in the lung in the low nanomolar range and through a competitive interaction. Serotonin and non-tricyclic serotonin uptake blockers inhibited [3H]imipramine binding in lung in a complex manner. Our results support the view that [3H]imipramine binding and the serotonin recognition site of the transporter are related but not identical.

Animals↗
PubMed1983

Dopamine receptors modulating [3H]acetylcholine release in slices of the cat caudate: effects of (-)-N-(2-chloroethyl)-norapomorphine.

(-)-N-(2-Chloroethyl)-norapomorphine [-)-NCA) inhibited in a concentration-dependent manner the electrically evoked [3H]acetylcholine release in slices of cat caudate. The inhibition by (-)-NCA was reversible and antagonized by the benzamide neuroleptic S-sulpiride. Although (-)-NCA is an irreversible antagonist at some behaviorally relevant postsynaptic dopamine receptors, its effect as an agonist on dopamine receptors modulating [3H]acetylcholine release strongly resembles its action on presynaptic dopamine autoreceptors modulating [3H]dopamine release. Our results suggest that the dopamine receptor modulating [3H]acetylcholine release may not be an appropriate in vitro model for those behaviorally relevant postsynaptic dopamine receptors which are antagonized by (-)-NCA. It is more likely that it conforms to the characteristics of presynaptic release-modulating dopamine autoreceptors. The agonistic action of (-)-NCA at presynaptic dopamine receptors, in contrast to the irreversible antagonism of some postsynaptic dopamine receptors by (-)-NCA, should be interpreted with caution. Evidence is presented which suggests that (-)-NCA breaks down in solution into (-)-N-(2-hydroxylethyl)-norapomorphine [-)-NHA). Since (-)-NHA is an agonist at presynaptic dopamine receptors, this physicochemical breakdown product may be partly responsible for the apparent agonistic properties of (-)-NCA under our in vitro conditions.

Acetylcholine↗
PubMed1983

Characterization of dopamine autoreceptor and [3H]spiperone binding sites in vitro with classical and novel dopamine receptor agonists.

The specific D2 receptor agonist, LY 141865, but not the specific D1-receptor agonist, SK&F 38393, potently inhibited electrically evoked [3H]dopamine release from slices of the cat caudate. Similarly, LY 141865, but not SK&F 38393, inhibited [3H]spiperone binding to membranes of the cat caudate. The inhibition by dopamine receptor agonists of electrically evoked [3H]dopamine release was antagonized by the specific D2-receptor antagonist S-sulpiride. The inhibition of the electrically evoked release of [3H]dopamine by apomorphine was not, however, antagonized by the specific D1-receptor antagonist, bulbocapnine. Similarly, S-sulpiride but not bulbocapnine potently inhibited [3H]spiperone binding to membranes of the cat caudate. These results suggest that the dopamine autoreceptor modulating the depolarization-evoked release of [3H]dopamine, and the binding site of [3H]spiperone, are valid in vitro models for D2-dopamine receptors. Contrary to some previous reports, DPI was inactive in both in vitro dopamine receptor models. The IC50 values of a series of dopamine receptor agonists correlated very well in the two in vitro dopamine receptor models. One exception to this correlation was bromocriptine, which was more potent at [3H]spiperone binding sites than at the dopamine autoreceptor. With the exception of bromocriptine, all dopamine receptor agonists had one-hundred fold higher potency at the dopamine autoreceptor than at [3H]spiperone binding sites. [3H]Spiperone binding sites are localized primarily postsynaptic to dopamine terminals. Possible differences between the pharmacological properties of pre- and postsynaptic dopamine receptors should become apparent in the comparison of the two in vitro dopamine receptor models. However, the order of potency of dopamine receptor agonists with both in vitro models, dopamine autoreceptor and [3H]spiperone binding, was the same: N-n-propylnorapomorphine greater than TL-99 = 7-HAT greater than M-7 greater than Apomorphine greater than LY 141865.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1983

Stereoisomers of apomorphine differ in affinity and intrinsic activity at presynaptic dopamine receptors modulating [3H]dopamine and [3H]acetylcholine release in slices of cat caudate.

We investigated the effects of R(-)-apomorphine and S(+)-apomorphine on dopamine receptors modulating electrically evoked [3H]dopamine and [3H]acetylcholine release from slices of cat caudate nucleus. R(-)-Apomorphine inhibited the release of both [3H]dopamine and [3H]acetylcholine with an IC50 of 20 nM, while S(+)-apomorphine was without inhibitory action on the electrically evoked release of either neurotransmitter at concentrations up to 1 microM. At a concentration of 1 microM, however, S(+)-apomorphine antagonized the inhibition by R(-)-apomorphine, producing a parallel five-fold shift to the right in the concentration-response curve to R(-)-apomorphine. These results indicate that S(+)-apomorphine is devoid of intrinsic activity to stimulate presynaptic dopamine receptors modulating the electrically evoked release of dopamine and acetylcholine. In addition, S(+)-apomorphine has an approximately ten-fold lower affinity for presynaptic dopamine receptors compared to R(-)-apomorphine.

Acetylcholine↗
PubMed1983

3H-Rauwolscine binding in platelets from depressed patients and healthy volunteers.

3H-Rauwolscine binds specifically and with high affinity to alpha 2-adrenoceptors in human platelets. In a study comparing the binding of 3H-rauwolscine in platelets obtained from 26 control volunteers with 19 hospitalised, untreated, severely depressed patients, the mean maximal binding (Bmax) and mean dissociation constant (Kd) of 3H-rauwolscine binding were found to be identical in both groups. After 7-12 days, treatment with different tricyclic antidepressant drugs there was a significant improvement in the depressive symptoms but no change in the 3H-rauwolscine binding. After an average of 23 days treatment with tricyclic antidepressants, and when the Hamilton Depression Rating Scores had returned to normal, the Kd and Bmax of 3H-rauwolscine binding were still unchanged.

Adjustment Disorders↗
PubMed1983

Amphetamine enhances latent dopaminergic neurotransmission in the rat striatum. Effects on 3H-acetylcholine release.

The electrically evoked, calcium-dependent release of 3H-acetylcholine from slices of rat striatum was inhibited in a concentration-dependent manner by (+)-amphetamine (0.2-20 microM). This inhibitory effect of (+)-amphetamine was unaffected by depletion of the endogenous stores of dopamine by pretreatment with reserpine (5 mg/kg, 24 h). However, the combined treatment of reserpine with alpha-methyl-p-tyrosine (300 mg/kg) or NSD 1015 (100 mg/kg) reduced significantly these inhibitory effects of (+)-amphetamine. Similar results were obtained after chronic 6-hydroxydopamine lesions of the corpus striatum. The inhibition of 3H-acetylcholine release by (+)-amphetamine in rats pretreated with reserpine was potentiated in the presence of 10 microM pargyline. These results support the view that the inhibitory effects of (+)-amphetamine on the electrically-evoked release of 3H-acetylcholine are mediated by dopamine released from a special pool of newly synthetized transmitter rather than through a direct action on an amphetamine recognition site or receptor.

Acetylcholine↗
PubMed1983

Complex inhibition of [3H]imipramine binding by serotonin and nontricyclic serotonin uptake blockers.

Tricyclic antidepressant drugs inhibit [3H]imipramine binding to the rat brain cortex in a competitive manner, giving linear Hofstee plots and Hill coefficients of approximately 1.0. Serotonin, the only neurotransmitter to inhibit [3H]imipramine binding, does so in a complex manner, exhibiting a Hill coefficient of 0.40-0.50. Nontricyclic inhibitors of serotonin uptake such as fluoxetine, paroxetine, norzimelidine, and citalopram inhibit [3H]imipramine binding in the same complex manner as serotonin. These results are interpreted as suggesting that [3H]imipramine binds to a site associated with the serotonin uptake system but different from either the substrate recognition site for serotonin or the site of action of the nontricyclic inhibitors of neuronal uptake of serotonin.

Amitriptyline↗
PubMed1983

Presynaptic alpha 2-adrenoceptor antagonism by verapamil but not by diltiazem in rabbit hypothalamic slices.

1 Rabbit hypothalamic slices prelabelled with [3H]-noradrenaline and superfused with Krebs solution were stimulated electrically at a frequency of 5 Hz. Exposure to verapamil (0.1 to 10 microM) significantly increased, in a concentration-dependent manner, the electrically-evoked overflow of tritium, without affecting the spontaneous outflow of radioactivity. 2 Exposure to diltiazem in concentrations up to 100 microM had no effect on the electrically evoked release of [3H]-noradrenaline, but increased the basal outflow of radioactivity at 10 and 100 microM. 3 The preferential alpha 2-adrenoceptor antagonist, yohimbine (0.1 microM) significantly antagonized the inhibitory effect of clonidine or adrenaline on [3H]-noradrenaline overflow elicited by electrical stimulation. Verapamil (3 microM) also antagonized this inhibitory effect of the alpha 2-adrenoceptor agonists on [3H]-noradrenaline release. In contrast to these results, exposure to diltiazem (10 microM) was ineffective in blocking the action of the alpha 2-adrenoceptor agonist. 4 These results suggest that the two Ca2+-antagonists verapamil and diltiazem differ in their ability to affect central noradrenergic neurotransmission. While verapamil is a relatively potent alpha 2-adrenoceptor antagonist, diltiazem is devoid of presynaptic alpha 2-adrenoceptor antagonist properties.

Adrenergic alpha-Antagonists↗
PubMed1983

Differential inhibition of vascular smooth muscle responses to alpha 1- and alpha 2-adrenoceptor agonists by diltiazem and verapamil.

This work was undertaken to investigate whether diltiazem and verapamil, two blockers of the voltage-activated calcium channel, interfered with vascular smooth muscle responses mediated by stimulation of alpha 1- or alpha 2-adrenoceptors. In pithed rats (and in isolated canine saphenous vein strips) cirazoline behaved as a preferential alpha 1-adrenoceptor agonist, since its pressor (and contractile) effects were blocked selectively by the alpha 1-adrenoceptor antagonist prazosin and were relatively unaffected by the alpha 2-adrenoceptor antagonist yohimbine. In the same preparations, M-7 (2,N,N-dimethylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene) exhibited preferential alpha 2-adrenoceptor agonist properties. The pressor response to M-7 developed much more slowly than that to cirazoline, M-7 requiring approximately twice as long as cirazoline to reach the same peak effect. Pithed rats received a 30-minute intravenous infusion of either diltiazem (12.5-25.0 micrograms/kg per min) or verapamil (6.2-12.5 micrograms/kg per min) that was continued while dose-response curves to M-7 and cirazoline were generated. These compounds depressed the maxima and the slopes of arterial pressure dose-response curves to M-7 but not cirazoline. In canine saphenous vein strips, diltiazem did not change the contractile response to cirazoline but inhibited those to M-7. Verapamil however did antagonize the responses to cirazoline although significantly less than those to M-7. These results indicate that diltiazem and verapamil preferentially inhibit alpha 2-adrenoceptor-mediated responses. The hypothesis is advanced that the pharmacomechanical coupling for alpha 2-adrenoceptors involves a receptor-operated calcium channel that is sensitive to diltiazem and verapamil and, thus, might become activated when the potential across the cellular membrane attains critical values.

Adrenergic alpha-Agonists↗
PubMed1983

Norepinephrine release and vascular response elicited by nerve stimulation in rats with chronic neurogenic hypertension.

In rats with chronic neurogenic hypertension induced by sinoaortic baroreceptors denervation (SAD), dl-[3H]norepinephrine (dl-[3H]NE) release, metabolism and vascular response to nerve stimulation were studied in isolated perfused mesenteric arteries. Thirty weeks after SAD, systolic arterial pressure was increased and, in isolated mesenteric arteries, vascular resistance, vascular response to nerve stimulation and responses to exogenous NE were higher in hypertensive than in sham-operated normotensive rats. However, in the isolated mesenteric arteries labeled with dl-[3H]NE, the total increase in radioactivity elicited by nerve stimulation was similar in both SAD and sham-operated groups. Unmetabolized [3H]NE released in mesenteric arteries was higher than that observed in other peripheral noradrenergic tissues (such as cat nictitating membrane, cat spleen, guinea-pig atria) and deaminated glycol 3,4-dihydroxyphenylglycol was the main metabolite of [3H]NE released by nerve stimulation from the mesenteric arteries of both groups. Blockade of prejunctional alpha adrenoceptors with phentolamine increased [3H]NE overflow to the same extent in controls and hypertensive rats. These findings indicate that the negative feedback regulatory mechanism for [3H]NE release mediated by prejunctional alpha adrenoceptors is not affected in chronic neurogenic hypertension. Blockade of postsynaptic alpha receptors by phentolamine reduced the vascular response equally in both groups. In hypertensive rats, a higher fraction of [3H]NE released by nerve stimulation was collected as the extraneuronally formed metabolite 3H-normetanephrine. The results suggest that, in rats with chronic neurogenic hypertension, sympathetic neurotransmission is not altered in the mesenteric arteries. Increased vasoconstrictor response to a given level of sympathetic nerve stimulation and higher resting vascular resistance could, in part, maintain the high blood pressure after 30 weeks of SAD.

Animals↗