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Biomedical subjects

A Pletscher

Publications and source records attributed to A Pletscher.

At least 73 records · Page 4Linked to original sources
PubMed1979

Shape change of blood platelets brought about by myelin basic protein and other basic polypeptides.

Basic proteins and polypeptides (BPP) such as myelin basic protein (MBP), polyornithine (M.W. 40,000), polylysine and protamine, which are known to cause neuronal depolarization in the central nervous system, induced a shape change reaction in blood platelets of various species, including man. This reaction was not accompanied by platelet aggregation or marked alterations of 5-hydroxytryptamine release. Cyclic nucleotide levels were also unchanged. The shape change induced by polyornithine was inhibited by heparin but not by antagonists of 5HT, catecholamines or gamma-aminobutryic acid, substances which are known to have no effect on the MBP-induced neuronal depolarization. Other basic substances, e.g. low molecular weight polyornithine (M.W. 4,000), cytochrome c, spermine and spermidine, did not induce either platelet shape change or (as shown before) neuronal depolarization. It is concluded, that 1) the shape change reaction of platelets seems to be a sensitive and simple means of detecting those BPP which induce functional changes in mammalian cells and 2) the use of platelets as models for neurons can be extended to include the action of BPP on the plasma membranes.

Animals↗
PubMed1979

Shape change of blood platelets--a model for cerebral 5-hydroxytryptamine receptors?

1. In blood platelets of rabbits isolated by a stractan gradient and incubated in a protein-poor medium, tryptamine, 5-hydroxytryptamine (5-HT) and derivatives, quipazine and mescaline caused a shape change. This shape change was inhibited by low concentrations of methysergide. 2. The most potent antagonists of the 5-HT-induced shape change included ergoline derivatives and neuroleptic drugs, which showed high stereoselectivity. 3. (+)-Lysergic acid diethylamide ((+)-LSD), psilocine and some N',N'-dimethylated tryptamines acted as mixed agonist-antagonists. 4. The compounds found to be agonists or mixed agonist-antagonists on platelets have previously been shown to act also as 5-HT agonists in the central nervous system (CNS). 5. With regard to 5-HT antagonists, the 5-HT receptors of platelets reacted differently from those described earlier in brain areas with dense 5-hydroxytryptaminergic innervation, but showed similarities to 5-HT receptors investigated previously in spinal cord, cerebral cortex and possibly reticular formation. 6. It is concluded that platelets may be considered with caution as models for some, but not for all, 5-HT receptors in the CNS.

Adenosine Diphosphate↗
PubMed1979

Uptake of 5-hydroxytryptamine in blood platelets and its inhibition by drugs: role of plasma membrane and granular storage.

The initial uptake of 3H-5-hydroxytryptamine (3H-5-HT) showed linearity for short time intervals in normal and reserpinized blood platelets of guinea-pigs, but was lower in reserpinized platelets. Teh Km values for the 3H-5-HT uptake were virtually identical in normal and reserpinized platelets, whereas Vmax was lower in the latter. Imipramine and chlorpromazine caused the same percentage inhibition of 3H-5-HT uptake in normal and reserpinized platelets; the reserpine-like compound Ro 4-1284 inhibited the uptake of 3H-5-HT in the normal, but not markedly in the reserpinized platelets. Haloperidol, prenylamine and Ro 4-9040 were more potent inhibitors in normal than in reserpinized platelets. It is concluded that (a) the Km of the initial uptake of 5-HT by platelets is probably determined by the mechanism at the plasma membrane, whereas Vmax may be codetermined by the intracellular storage capacity, (b) platelets are models for differentiating the site of action (plasma membrane or storage organelles) of drugs interfering with 5-HT uptake, and (c) neuroleptics- and reserpine-like compounds may either act selectively on the plasma membrane or on the intracellular storage organelles, or affect both of these subcellular sites.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1979

Blood platelets as models for central 5-hydroxytryptaminergic neurons.

Blood platelets resemble 5-hydroxytryptamine (5HT) neurons of the central nervous system (CNS) with regard to uptake kinetics of 5HT at the plasma membrane and potencies of 5HT uptake inhibitors at this membrane. Furthermore, by comparing 5HT uptake in normal and reserpinized platelets the site of action of uptake inhibitors (plasma membrane, intracellular amine storage organelles) may be determined. The specific 5HT receptors of platelets whose stimulation induces a reversible shape change of platelets seem to react to drugs in a similar way as 5HT receptors of some CNS-regions such as spinal cord, cortex and possibly reticular formation. In other CNS areas e.g. those with dense 5HT innervation and the hippocampus the 5HT receptors show a reaction to drugs which is partially different from that of the platelet receptors. In other respects e.g. the synthesis and turnover of 5HT platelets do not resemble 5HT neurons. It is concluded that platelets may be used with caution as models for 5HT-neurons with regard to some aspect of 5HT-dynamics.

Animals↗
PubMed1979

[Neurohumoral transmitter mechanisms at the cellular level].

The term neurohumoral transmission designates the transfer of a nerve impulse from a presynaptic to a postsynaptic neuron by means of a humoral agent e.g. a biogenic amine, an amino acid or a peptide. This process involves several steps, i.e. biosynthesis, storage, release, receptor interaction and inactivation of the transmitter. A neuromodulator modifies, for instance the release of a transmitter by action on a presynaptic transmitter neuron. Biogenic amines may also be released from non-synaptic nerve terminals and possibly exert a modulatory effect on other neurons. The regulation of the transmitter dynamics at the enzymatic level occurs by end-product inhibition and by enzyme induction. In addition, there are regulatory mechanisms originating from autoreceptors and postsynaptic receptors which operate via feedback action. Stimulation or inhibition of receptors may lead to receptor sub- and supersensitivity respectively. Numerous neuro-psychotropic drugs used in medical practice act on the various steps of neurohumoral transmission and thereby influence the dynamics of neurotransmitters and modulators.

Animals↗
PubMed1977

Increase of striatal dopamine turnover by drugs: interference with granular storage or receptor blackade?

Apomorphine completely antagonized the reserpine-induced enhancement of the striatal 3,4-dihydroxyphenylalanine (dopa) accumulation seen after administration of the decarboxylase inhibitor 3-hydroxybenzylhydrazine (NSD 1015). Reserpine-like drugs, e.g. Ro 4-1284 and Ro 4-9040, markedly enhanced the striatal dopa accumulation (due to NSD 1015) in normal animals but not in rats treated with reserpine plus apomorphine. Haloperidol enhanced the striatal dopa accumulation to a similar extent in normal and in reserpine-apomorphine-treated animals. Chlorpromazine also caused an enhancement of striatal dopa accumulation in both types of animals, but its potency was somewhat higher in normal rats than in those treated with reserpine plus apomorphine. In conclusion, reserpinized animals treated with apomorphine appear to be useful models for differentiating whether a drug enhances striatal DA turnover by interference with granular DA storage or by blockade of DA receptors. The latter seems to be the main mechanism of action of neuroleptic drugs.

Animals↗
PubMed1977

Effect of neuroleptics and other drugs on monoamine uptake by membranes of adrenal chromaffin granules.

1 The effects have been investigated of various reserpine-like, neuroleptic, antidepressant and other compounds on the adenosine-5'-triphosphate (ATP)-dependent uptake of noradrenaline (NA) (reserpine-sensitive) and tryptamine (reserpine-resistant) by membranes of isolated chromaffin granules of bovine adrenal medulla. 2 Reserpine and Ro 4-1284 (2-hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-hexahydro-11bH-benzo(a)quinolizine) as well as neuroleptics (e.g. chlorpromazine and haloperidol) inhibited the NA uptake, but the reserpine-like drugs were more potent. In contrast, Ro 4-1284 showed a considerably weaker effect thatn the neuroleptics in interfering with tryptamine uptake. Chlorpromazine had about the same potency in inhibiting NA and tryptamine uptake, whereas the action of haloperidol was more pronounced on the uptake of NA than of tryptamine. 3 The relative potencies of neuroleptic drugs in inhibiting NA uptake by granule membranes in vitro corresponded only partly to their relative potencies in enhancing dopamine turnover in vivo. 4 The inhibition of NA uptake by chloropromazine and Ro 4-1284 appeared to be of the noncompetitive type. 5 Chlorpromazine did not influence the decrease in ATP induced by granule membranes in the incubation medium. 6 Other basic, but not acidic compounds also inhibited NA uptake by granule membranes; their potency was of the order of that of chlorpromazine (antidepressants) or weaker (e.g. benzodiazepines). 7 In conclusion, the mechanism of action of neuroleptics probably differs from that of reserpine-like drugs in the inhibition of monoamine uptake by membranes of catecholamine storage organelles. While interference with the granular storage of dopamine at the granule membrane level may contribute to the in vivo action of neuroleptics (e.g. in enhancing dopamine turnover), additional effects of these drugs must be involved in vivo, e.g. blockade of pre- and postsynaptic dopamine receptors.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1977

Mepacrine, a tool for investigating the 5-hydroxytryptamine organelles of blood platelets by fluorescence microscopy.

In the blood platelets of various species exposed to mepacrine, the average number of green-yellow fluorescent granules (probably identical with the 5-hydroxytryptamine [5-HT] storage organelles) corresponded to that of flashes emitted by the platelets on prolonged irradiation with violet-blue light. In platelets of fawn-hooded rats the number of granules did not markedly differ from that of normal rat platelets, but the fluorescence intensity and the uptake of mepacrine in vitro showed a marked decrease and the flashes were less numerous. The heavy population of human platelets exhibited considerably more granular structures than the light population. The data suggest that (1) in normal, mepacrine-loaded platelets one flash corresponds to one 5-HT organelle and (2) mepacrine is a useful tool for investigating the number and function of the 5-HT organelles in live platelets and possibly for studying platelet age.

Animals↗
PubMed1976

Uptake and liberation of mepacrine in blood platelets.

1. Isolated platelets of guinea pigs incubated in Tyrode showed a rapid accumulation of 14C-mepacrine which was less dependent on temperature than that of 14C-5-hydroxytryptamine (5HT). 2. The uptake of mepacrine was not inhibited by imipramine, cocaine, ouabain, KCN, NaF, and reserpine. 3. Various 5HT-liberating drugs, e.g. Ro 4-1284 (benzoquinolizine derivative with reserpine-like action), amphetamine, tyramine and imipramine did not markedly affect the 14C-mepacrine content of platelets previously loaded with this compound. 4. Thrombin and chlorpromazine caused a liberation of 14C-mepacrine from the platelts which was however, less pronounced than that of 14C-5HT. 5. From these and previous findings it is concluded that 14C-mepacrine accumulates in the 5HT storage organelles by a reserpine-insensitive mechanism not dependent on an active transport at the cytoplasmatic membrane level.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1976

Subcellular localization of the heparin-neutralizing factor in blood platelets.

1. The distribution of the heparin-neutralizing factor (platelet factor 4, PF4) in subcellular organelles of blood platelets of rabbits and man was investigated. 2. In both species the organelles storing 5-hydroxytryptamine (5-HT storage organelles) contained only trivial amounts of PF4. 3. In contrast, the content of PF4 was highest in the subcellular fractions rich in alpha-granules. 4. In conclusion, PF4 is probably localized in the alpha-granules and therefore the platelets contain at least two types of organelles (5-HT organelles and alpha-granules) capable of releasing their contents in response to the same stimuli, such as exposure to collagen, thrombin, etc.

Animals↗