Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possible involvement of ATP, in addition to noradrenaline, in nicotine-evoked vasoconstriction was studied in branches of the ileocolic artery of the rabbit. For measurement of vasoconstrictor responses, the arteries were simultaneously incubated and perfused. For measurement of the release of [3H]-noradrenaline, they were preincubated with [3H]-noradrenaline and then superfused. Prazosin (0.1 mumol/l) antagonized the constrictor effect of exogenous noradrenaline but not that of exogenous ATP. Desensitization of P2X-receptors by alpha, beta-methylene ATP markedly attenuated the effect of exogenous ATP but not that of noradrenaline. The presumed P2-purinoceptor antagonist suramin (100 mumol/l) reduced the maximal contraction obtainable with noradrenaline and shifted the concentration-response curve for the constrictor effect of alpha, beta-methylene ATP to the right, but did not change the effect of ATP. Nicotine elicited monophasic vasoconstrictions which faded while nicotine was still in the medium. The concentration-response curve was bell-shaped with an EC50 of 50 mumol/l and a maximal effect at 180 mumol/l, and the exposure time-response curve indicated that responses were maximal after 5 s of contact of nicotine (180 mumol/l) with the tissue. Neither prazosin 0.1 mumol/l nor desensitization by alpha,beta-methylene ATP changed the time course of the response to nicotine, but both depressed the magnitude of the responses over the whole concentration- and exposure time-response curves. The depression was greater with prazosin than with alpha,beta-methylene ATP. Desensitization by alpha,beta-methylene ATP or addition of suramin 100 mumol/l practically abolished the prazosin-resistant part of the response. The effect of nicotine was blocked by hexamethonium as well as by sympathetic denervation by 6-hydroxydopamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adrenergic and purinergic cotransmission in nicotine-evoked vasoconstriction in rabbit ileocolic arteries. 194 11

1. Using a grease-gap recording technique we have investigated the effects of some antagonists of P2-purinoceptors on the depolarization of the rat isolated superior cervical ganglion evoked by 100 microM alpha, beta-methylene-adenosine 5'-triphosphate (alpha,beta-MeATP) or uridine 5'-triphosphate (UTP). The effects of the putative P2Z-purinoceptor antagonist, coomassie brilliant blue G, putative P2X-purinoceptor antagonist, 4,4'-diisothiocyanatostilbene-2,2'-disulphonate (DIDS) and uniblue A (an analogue of the P2Y- and P2X-purinoceptor antagonist reactive blue 2) were investigated. 2. At the highest concentration examined uniblue A (300 microM) depressed alpha,beta-MeATP-induced depolarization and at 100 and 300 microM enhanced UTP-evoked depolarizations. Coomassie brilliant blue G (1 and 10 microM) did not affect depolarizations evoked by alpha,beta-MeATP or UTP. Depolarizations evoked by potassium (5 mM) or muscarine (100 nM) were unaltered by either coomassie brilliant blue G or uniblue A. Uniblue A (100 and 300 microM) produced a concentration-dependent depression of hyperpolarizations evoked by adenosine (100 microM) whereas coomassie brilliant blue G at up to 10 microM, did not alter adenosine-induced hyperpolarizations. 3. DIDS (30 and 100 microM) did not alter adenosine-evoked hyperpolarizations, or depolarizations evoked by potassium or UTP. DIDS at 100 microM did not alter depolarizations evoked by muscarine. In contrast DIDS produced a concentration-dependent depression of alpha,beta-MeATP-evoked depolarizations. 4. These results are consistent with the proposal that uniblue A and DIDS but not coomassie brilliant blue G are antagonists of P2-purinoceptors and that uniblue A is also an antagonist at P1-purinoceptors present on the rat superior cervical ganglion. 5. The ability of uniblue A and DIDS to distinguish between depolarizations evoked by UTP and alpha,beta-MeATP provides further justification for the proposal that these nucleotides activate separate receptors present on the rat superior cervical ganglion, i.e. pyrimidinoceptors and P2-purinoceptors respectively.
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PMID:Discrimination between UTP- and P2-purinoceptor-mediated depolarization of rat superior cervical ganglia by 4,4'-diisothiocyanatostilbene-2,2'- disulphonate (DIDS) and uniblue A. 758 53

1. The role of endogenous ADP in platelet aggregation in vivo remains unclear due to the lack of suitable P2T-antagonist probes. This paper describes the potency, selectivity and specificity of the novel P 2T-purinoceptor antagonist, FPL 67085 (2-propylthio-D-beta,gamma-dichloromethylene ATP) both in vitro and in the anaesthetized rat in vivo. 2. FPL 67085 (3-30 nM) produced concentration-dependent rightward displacement of the concentration-effect (E/[A]) curve for ADP-induced aggregation of human washed platelets with no effect on ADP-independent aggregation at < or = 10 microM. 3. Logistic fitting of ADP E/[A] data indicated that the antagonist effect of FPL 67085 did not consistently accord with simple competition: in some preparations depression of the asymptote was seen. Schild analysis of data combined from all preparations, regardless of the antagonist profile observed, gave an apparent pKB of 8.9 (slope parameter 0.90). 4. The potency of FPL 67085 was unaffected by the P1-purinoceptor antagonist, 8-sulphophenyltheophylline, was similar (IC50 0.6-3.8 nM) in human and rat washed platelets or whole blood and, in rat blood, did not change following 2-30 min incubation at 37 degrees C. 5. FPL 67085 was a weak (pA50 approximately 4.2) partial agonist in tissues containing P2X- or P2Y-purinoceptors, indicating some 30,000 fold selectivity for the P2T-subtype. 6. In anaesthetized rats, intravenous infusion of FPL 67085 produced rapidly-reversible, dose-related inhibition of ADP-induced platelet aggregation measured ex vivo (ID50 1.3 micrograms kg-1 min-1) with no significant effect on haemodynamics or circulating cell counts. 7. Thus, FPL 67085 is a potent, specific and selective inhibitor of ADP-induced platelet aggregation both in vitro and in vivo. As such, it represents a novel pharmacological tool to define the role of endogenous ADP in thrombosis and the potential of P2T-purinoceptor antagonists as a novel class of infusible anti-thrombotic agents for acute use in man.
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PMID:Pharmacological profile of the novel P2T-purinoceptor antagonist, FPL 67085 in vitro and in the anaesthetized rat in vivo. 758 10

Rabbit atria were isolated with the extrinsic right sympathetic and vagus nerves attached and perfused with Tyrode solution. Acetylcholine overflow was determined after labelling of the transmitter stores with [14C]choline and fractionation of the radioactivity on cation exchange columns. Sympathetic nerve stimulation (SNS, 2 Hz, 3 min) carried out together with vagus nerve stimulation (VNS, 2 Hz, 3 min), but each SNS pulse preceding a vagal one by 19 ms, caused a facilitation of acetylcholine overflow of about 60% versus independent controls in the absence of SNS. Antagonists of putative neurotransmitters were tested to find out the prejunctional mediator involved in the facilitation. The facilitation was not significantly reduced by prazosin, rauwolscine, idazoxan, or propranolol, excluding mediation by alpha- or beta-adrenoceptors. However, guanethidine abolished evoked noradrenaline release and facilitation, suggesting that it is due to a compound co-released with noradrenaline from postganglionic noradrenergic nerves. Pretreatment of rabbits with reserpine which reduced noradrenaline content of atria and SNS evoked overflow by 94% did not affect the facilitation of acetylcholine release which, due to the cardiostimulatory action of SNS being absent, resulted in enhanced depression of atrial force. We conclude that the facilitation is due to release of a reserpine-resistant co-transmitter from sympathetic nerves. Possible mediation of the facilitation by ATP through P2X- or P2Y-purinoceptors was excluded by ineffectiveness of alpha, beta-methylene ATP-preperfusion, of suramin and cibacron blue, respectively. However, the selective A2 adenosine receptor antagonist CP 66,713 reduced the facilitation by 25% whereas DPCPX (A1-selective) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Co-transmitter mediated facilitation by sympathetic nerve stimulation of evoked acetylcholine release from the rabbit perfused atria preparation. 777 98

Effects of eight small aromatic isothiocyanato-sulphonates, of the aliphatic 2-isothiocyanatoethene-1-sulphonate (IES), and of the parent amines were studied on contractions of the rat vas deferens elicited by alpha, beta-methylene ATP (alpha, beta-MeATP; mediated by P2X-purinoceptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S; mediated by P2Y-purinoceptors), and the degradation of ATP by rat vas deferens tissue. The aromatic isothiocyanato-sulphonates all reduced contractions of the rat vas deferens elicited by alpha, beta-methylene ATP. The antagonism was non-competitive, with depression of the maximum of the concentration-response curve of alpha, beta-MeATP and incomplete reversibility. The IC50 values were between 11 and 54 microM. In the guinea pig taenia coli, the aromatic compounds shifted the concentration-response curve of ADP beta S to the right in a surmountable manner (one exception), and where three concentrations were tested, the Arunlakshana-Schild regression was linear and its slope did not differ from 1. The apparent Kd values were between 10 and 214 microM. The removal of ATP from the medium by vas deferens tissue was decreased by the aromatic isothiocyanates with IC25% values between 25 and 464 microM. IES and the parent amines were inactive or almost inactive (parent amines not tested on ATP breakdown). The results indicate that the isothiocyanato residue as well as the aromatic core are essential for P2-purinoceptor blockade. At the P2X-purinoceptor, potency increases with the size of the molecules but is independent of the position of the isothiocyanato and sulphonate substituents. No simple structure-activity relationship for the P2Y-purinoceptor and the ATP-degrading ecto-nucleotidases can be derived beyond the apparent lack of a major influence of the position of the substituents. 2-Isothiocyanatonaphthalene-1-sulphonate (beta-INS) seems to be interesting because of relatively high P2X-selectivity versus both the P2Y-purinoceptor and ecto-nucleotidases.
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PMID:P2-purinoceptor antagonists: I. Blockade of P2-purinoceptor subtypes and ecto-nucleotidases by small aromatic isothiocyanato-sulphonates. 889 52

It has been reported that suramin, an anthelminthic, trypanocidal agent and an inhibitor of P2 receptors, may antagonise N-methyl-D-aspartate (NMDA) subtype of the excitatory amino acid receptors. Both NMDA receptors and P2X subclass of P2 receptors are ligand-gated Ca2+-selective channels and, since the increased influx of Ca2+ into neurons has been linked to neurotoxicity, simultaneous inhibition of P2X and NMDA receptors in vivo by suramin could represent an effective neuroprotective treatment. We have found that suramin inhibited the binding of [3H]CGP 39653 to NMDA receptor binding sites in vitro and reduced the frequency of NMDA channel openings in patch-clamp studies. Suramin (1 mM) had no effect on [3H]kainate binding in vitro. In vivo, intracerebroventricular (I.C.V.) injections of suramin (70 nmol/brain) antagonised convulsive effects of the NMDA agonist (RS)-(tetrazol-5-yl)-glycine (TZG, LY 285265). Suramin, however, did not prevent neurotoxic lesions in the hippocampus caused by I.C.V. administration of TZG. Increasing the dose of suramin resulted in death from severe respiratory depression.
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PMID:P2 purinoceptor blocker suramin antagonises NMDA receptors and protects against excitatory behaviour caused by NMDA receptor agonist (RS)-(tetrazol-5-yl)-glycine in rats. 930 84

1. Hippocampal slices (450 microm) generate epileptiform bursts of an interictal nature when perfused with a zero magnesium medium containing 4-aminopyridine (50 microM). The effect of adenine nucleotides on this activity was investigated. 2. ATP and adenosine depressed this epileptiform activity in a concentration-dependent manner, with both purines being equipotent at concentrations above 10 microM. 3. Adenosine deaminase 0.2 u ml(-1), a concentration that annuls the effect of adenosine (50 microM), did not significantly alter the depression of activity caused by ATP (50 microM). 4. 8-Cyclopentyl-1,3-dimethylxanthine (CPT), an A1 receptor antagonist, enhanced the discharge rate significantly and inhibited the depressant effect of both ATP and adenosine such that the net effect of ATP or adenosine plus CPT was excitatory. 5. Several ATP analogues were also tested: alpha, beta-methyleneATP (alpha, beta-meATP), 2-methylthioATP (2-meSATP) and uridine triphosphate (UTP). Only alpha, beta-meATP (10 microM) produced an increase in the frequency of spontaneous activity which suggests a lack of involvement of P2Y or P2U receptors. 6. Suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), P2 receptor antagonists, failed to inhibit the depression produced by ATP (50 microM). The excitatory effect of alpha, beta-meATP (10 microM) was inhibited by suramin (50 microM) and PPADS (5 microM). 7. ATP therefore depresses epileptiform activity in this model in a manner which is not consistent with the activation of known P1 or P2 receptors, suggesting the involvement of a xanthine-sensitive nucleotide receptor. The results are also indicative of an excitatory P2X receptor existing in the hippocampal CA3 region.
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PMID:Modulation by adenine nucleotides of epileptiform activity in the CA3 region of rat hippocampal slices. 948 56

1. The effects of exogenous ATP or adenosine on end-plate currents (e.p.cs; evoked by simultaneous action of a few hundred quanta of ACh) or on miniature e.p.cs (m.e.p.cs) were studied under voltage clamp conditions on frog sartorius muscle fibres. 2. ATP or adenosine (100 microM(-1) mM) reduced the e.p.c. amplitude but did not affect m.e.p.c. amplitude, decay time constant and voltage-dependence of m.e.p.c., suggesting that e.p.c. depression induced by these purines had presynaptic origin only. 3. The action of ATP, unlike that of adenosine, was prevented by the P2-purinoceptor antagonist suramin (100 microM). The stable ATP analogue alpha,beta-methylene ATP (100 microM), known to be desensitizing agent on P2X receptors, also abolished the depressant effect of ATP while sparing the action of adenosine. Concanavalin A, an inhibitor of ecto-5'-nucleotidase, did not affect the presynaptic action of exogenously applied ATP. 4. The presynaptic action of adenosine was prevented by theophylline (1 mM), a blocker of adenosine receptors, while the effect of ATP was not changed under these conditions. The selective blocker of A1 adenosine receptors, 8-cyclopentyl-1,3,dipropylxanthine (DPCPX; 0.1 microM), abolished the presynaptic action of adenosine but did not prevent the depressant effect of ATP. 5. The effects of ATP and adenosine (at nearly saturating concentration) were additive suggesting that these purines activated not only distinct receptors but also different intracellular signalling mechanisms. 6. In contrast to the hypothesis that at the neuromuscular junction ATP reduces transmitter release via enzymatic degradation to presynaptically active adenosine, our data suggest that ATP (through its own presynaptic receptors) directly inhibits ACh release. Thus, ATP and adenosine might be almost equipotent as endogenous prejunctional neuromodulators at the neuromuscular junction.
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PMID:ATP and adenosine inhibit transmitter release at the frog neuromuscular junction through distinct presynaptic receptors. 969 Aug 79

The distribution of the P2X2 receptor subunit of the adenosine 5'-triphosphate (ATP)-gated ion channels was examined in the adult rat central nervous system (CNS) by using P2X2 receptor-specific antisera and riboprobe-based in situ hybridisation. P2X2 receptor mRNA expression matched the P2X2 receptor protein localisation. An extensive expression pattern was observed, including: olfactory bulb, cerebral cortex, hippocampus, habenula, thalamic and subthalamic nuclei, caudate putamen, posteromedial amygdalo-hippocampal and amygdalo-cortical nuclei, substantia nigra pars compacta, ventromedial and arcuate hypothalamic nuclei, supraoptic nucleus, tuberomammillary nucleus, mesencephalic trigeminal nucleus, dorsal raphe, locus coeruleus, medial parabrachial nucleus, tegmental areas, pontine nuclei, red nucleus, lateral superior olive, cochlear nuclei, spinal trigeminal nuclei, cranial motor nuclei, ventrolateral medulla, area postrema, nucleus of solitary tract, and cerebellar cortex. In the spinal cord, P2X2 receptor expression was highest in the dorsal horn, with significant neuronal labeling in the ventral horn and intermediolateral cell column. The identification of extensive P2X2 receptor immunoreactivity and mRNA distribution within the CNS demonstrated here provides a basis for the P2X receptor antagonist pharmacology reported in electrophysiological studies. These data support the role for extracellular ATP acting as a fast neurotransmitter at pre- and postsynaptic sites in processes such as sensory transmission, sensory-motor integration, motor and autonomic control, and in neuronal phenomena such as long-term potentiation (LTP) and depression (LTD). Additionally, labelling of neuroglia and fibre tracts supports a diverse role for extracellular ATP in CNS homeostasis.
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PMID:Distribution of the P2X2 receptor subunit of the ATP-gated ion channels in the rat central nervous system. 1021 85

The effects of hibernation on endothelium-dependent vasodilatation were investigated in the golden hamster carotid artery, paying special attention to hibernating body temperature (10 degrees C). To record mechanical and electrical membrane responses, we applied pharmacological (organ bath) and electrophysiological (microelectrode) techniques, using acetylcholine (ACh; 0.001-100 microM) and ATP (0.01-1000 microM) for endothelium-dependent vasodilatation and sodium nitroprusside (SNP; 0.05-10 microM) for endothelium-independent vasodilatation. At 34 degrees C, ACh, ATP and SNP each induced a relaxation or a hyperpolarization, and these responses were similar in all the preparations from control and hibernated animals. At 10 degrees C, on the other hand, ACh-induced relaxations and hyperpolarizations were reduced to approximately 35 % and 50 % of the euthermic level in controls and 1 % and 4 % of the euthermic level in hibernated animals, respectively. In contrast, at 10 degrees C, ATP induced only a contraction or depolarization in all preparations with no significant difference between control and hibernated animals. SNP-induced relaxations and hyperpolarizations obtained at 34 degrees C were not attenuated by cooling to 10 degrees C. In the presence of a P2X receptor blocker, pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 5 microM), at 34 degrees C ATP-induced relaxations and hyperpolarizations were significantly enhanced whereas no responses were induced by ATP at 10 degrees C. After endothelium removal, on the other hand, ATP induced only a contraction or depolarization at both 34 degrees C and 10 degrees C. These results suggest that depression of endothelium-dependent vasodilator responses to ACh and ATP may occur in the hibernating golden hamster carotid artery.
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PMID:Reversible impairment of endothelium-dependent relaxation in golden hamster carotid arteries during hibernation. 1192 87


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