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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The depression of monosynaptic excitation of neonatal rat motoneurones by (1S,3S)- and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD) and by L-2-amino-4-phosphonobutyrate (L-AP4), which is probably presynaptically mediated, is antagonized by (+/-)- and (+)-alpha-methyl-4-carboxyphenylglycine (MCPG). The same phenylglycine derivatives also antagonize the depression of forskolin-stimulated cyclic AMP synthesis effected by the two ACPD stereoisomers and by L-AP4. These results support previous suggestions that presynaptic depression is mediated by metabotropic glutamate receptors negatively coupled to adenylyl cyclase activity. MCPG is the first antagonist to be reported for these receptors.
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PMID:Antagonism of presynaptically mediated depressant responses and cyclic AMP-coupled metabotropic glutamate receptors. 815 72

We hypothesized that halothane-induced depression of airway smooth muscle (AWSM) contractility is caused, in part, by an effect on pertussis toxin-sensitive guanosine triphosphate (GTP)-binding regulatory proteins (G proteins). To determine the effect of G protein inactivation on the ability of halothane to relax AWSM, isolated strips of canine tracheal smooth muscle were contracted with the muscarinic agonist acetylcholine and relaxed by halothane (0.2 to 1.6 minimum alveolar anesthetic concentration [MAC]). Half of the strips were treated with pertussis toxin 10 micrograms/mL. Because a pertussis toxin-sensitive G protein mediates muscarinic inhibition of adenylyl cyclase, depression of G protein function by halothane might also enhance the relaxing effects of beta-adrenoreceptor agonists. To test this possibility, in another series of experiments, the effect of pretreatment with 1.6 MAC halothane on the ability of isoproterenol to relax strips contracted with acetylcholine was studied; the converse order of drug presentation was also performed. Treatment with pertussis toxin did not affect the ability of halothane to relax AWSM; 1.6 MAC halothane produced a 42% +/- 8% (mean +/- SD) and 38% +/- 8% decrease in force in treated and untreated strips, respectively. Exposure to 1.6 MAC halothane did not significantly affect the dose-response relationship between isoproterenol and force. Conversely, exposure to isoproterenol (0.036 +/- 0.033 micron) did not significantly affect the dose-response relationship between halothane and force. These results do not support the presence of a significant effect of halothane on the function of pertussis toxin-sensitive G proteins.
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PMID:Halothane and pertussis toxin-sensitive G proteins in airway smooth muscle. 831 Dec 86

Clinical myocardial dysfunction following cardiopulmonary bypass commonly occurs in patients with good preoperative ventricular function. Following separation from cardiopulmonary bypass, ventricular function improves initially, but then begins to worsen and reaches a nadir between 4 and 6 hours after surgery with full recovery occurring around 24 hours postoperatively. However, in patients with preoperative ventricular dysfunction, the depression of ventricular function is more severe and recovery is longer. Despite this high frequency of myocardial dysfunction, many patients do well without requiring pharmacologic intervention after cardiopulmonary bypass to augment contractility and peripheral perfusion. Factors that may predict the need for inotropic support in patients following cardiopulmonary bypass include low ejection fraction, older age, cardiac enlargement, female sex, the length of cardiopulmonary bypass and the duration of aortic cross-clamping. The patient with preoperative ventricular dysfunction has many of these preoperative and intraoperative predictors for inotropic support. The pharmacologic regimen to support the myocardium during the recovery period following cardiopulmonary bypass must take into consideration the pathophysiologic processes of chronic congestive heart failure and reperfusion injury. Reduction of cyclic adenosine monophosphate (cAMP) levels is a fundamental problem in congestive heart failure and results from either down-regulation of beta-receptors or a defect in the G-regulatory proteins controlling adenylyl cyclase production. This diminishes the effectiveness of agents dependent on cAMP to produce an inotropic response. However, amplification of the reduced cAMP produced by beta-agonists may occur in association with the inhibition of cAMP breakdown resulting from phosphodiesterase inhibitors. All inotropic agents are usually effective in reversing the reperfusion-induced stunned myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myocardial dysfunction following cardiopulmonary bypass: recovery patterns, predictors of inotropic need, theoretical concepts of inotropic administration. 836 65

In isolated rat hearts the calcium paradox, induced by perfusion for 3 minutes in the absence of calcium followed by perfusion for 10 minutes in the presence of calcium, depressed the activation of adenylyl cyclase by l-isoproterenol, NaF and forskolin. The characteristics of the beta-adrenoceptors and the activation of adenylyl cyclase by guanylyl imidodiphosphate were not changed. The findings suggest an uncoupling of beta-adrenoceptors from the catalytic site of the adenylate cyclase complex. Diltiazem, at 0.4 microM in the perfusion medium, greatly reduced the diminution of the activation of adenylate cyclase by isoproterenol and forskolin, and completely prevented the depression of the activation of adenylate cyclase by NaF. These effects may be due to interference by diltiazem with the mechanisms that promote an excessive influx of calcium into the heart during the calcium paradox.
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PMID:Diltiazem prevents the depression of adenylyl cyclase activity induced by the calcium paradox in rat. 840 22

Numerous studies have clearly shown that the turnover and release of serotonin (5-hydroxytryptamine, 5-HT) are increased under acute stressful conditions. Inasmuch as this latter process is under the control of a feedback mechanism involving the stimulation of presynaptic 5-HT1B autoreceptors, we have investigated the possible effects of acute restraint (40 min) on the functional properties of 5-HT1B receptors. The efficacy of the selective 5-HT1B receptor agonist 3-[1,2,5,6-tetrahydropyrid-4-yl]pyrrolo-[3,2-b]pyrid-5-one (CP-93,129) in inhibiting in vitro the K+-evoked release of [3H]5-HT, was significantly reduced in stressed rats as compared to naive animals. Similarly, the responsiveness of 5-HT1B receptors inhibiting the release of [3H]acetylcholine (presynaptic 5-HT1B heteroreceptors), was reduced by restraint. These effects were observed in the hippocampus, but using the inhibitory effect of CP-93,129 on forskolin-stimulated adenylyl cyclase activity as an index of 5-HT1B receptor function, it could be shown that the 5-HT1B receptors located in the substantia nigra are also desensitized by stress. The number as well as the apparent affinity constant of 5-HT1B binding sites labelled by [125I]iodocyanopindolol, as measured by quantitative autoradiography and membrane binding, were similar in naive and restraint-stressed rats suggesting that the stress-induced desensitization of 5-HT1B receptors is not due to a reduced number of 5-HT1B binding sites. As stress is thought to be a causal factor for the etiology of anxiety and depression, these results support the potential involvement of 5-HT1B receptor dysfunction in the development of these neurological disorders.
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PMID:Effects of stress on the functional properties of pre- and postsynaptic 5-HT1B receptors in the rat brain. 875 Jul 15

1. A characteristic feature of vasoconstrictor 5-HT1-like receptors in vitro is that responses mediated by these receptors are enhanced by other vasoconstrictor agents. In the present study, we have examined the influence of cellular cyclic AMP on vasoconstrictor responses to activation of 5-HT1-like receptors in isolated ring segments of the rabbit femoral artery (RbFA), and determined whether modulation of this second messenger underlies the ability of angiotensin II, an endogenous vasoconstrictor, to enhance 5-HT1-like responses. 2. In the presence of 0.1 microM ketanserin (to antagonize 5-HT2-receptors) and 0.3 microM prazosin (to antagonize alpha 1-adrenoceptors), 5-HT produced a concentration-related contraction, which was significantly augmented by pre-contraction of the vessel with 0.1-0.45 nM ([A30]) angiotensin II. Responses to 5-HT in the presence of angiotensin II were inhibited by the 5-HT1-like/5-HT2 antagonist, metergoline (1 microM). 3. The directly-acting adenylyl cyclase activator, forskolin (1 microM), abolished responses to angiotensin II and caused a rightward shift and concomitant depression of the 5-HT concentration-effect (E/[A]) curve. Higher concentrations of forskolin (> 10 microM) abolished responses to 5-HT and 1 microM sodium nitroprusside abolished responses to 5-HT and angiotensin II (n = 7). 4. In the presence of angiotensin II (0.1-0.45 nM), however, 1 microM forskolin failed to inhibit 5-HT-induced contractions; the E/A curve for 5-HT (in the presence of forskolin and angiotensin II) was not significantly different from that produced in the presence of angiotensin II alone. Similarly, the presence of angiotensin II (0.1-0.45 nM) was also able to overcome partially the inhibitory effect of 1 microM sodium nitroprusside against 5-HT-induced contractions (n = 7). In marked contrast, 5-HT failed to elicit a contraction in the presence of angiotensin II and 10 microM forskolin (n = 5). 5. 5-HT (1 microM) significantly reduced basal cyclic AMP accumulation by 35%, whereas angiotensin II (0.45 nM) was without effect. The combination of angiotensin II and 5-HT failed to alter significantly the reduction in cyclic AMP produced by 5-HT alone. Forskolin (1 microM) increased cyclic AMP levels 7 fold above basal, but neither 1 microM 5-HT nor a combination of 1 microM 5-HT and 0.45 nM angiotensin II produced a significant decrease in cyclic AMP content. 6. Whilst moderate concentrations of forskolin can inhibit the responses to either agent, simultaneous activation of angiotensin II and 5-HT1-like receptors can overcome the inhibitory effect of elevated levels of cyclic AMP. Since the potentiating effect of angiotensin II, in either the presence or absence of forskolin, occurs without significant alteration of cellular cyclic AMP, it seems likely that a cyclic AMP-independent pathway is implicated in the synergistic interaction between angiotensin II and vasoconstrictor 5-HT1-like receptors.
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PMID:The effect of forskolin on 5-HT1-like and angiotensin II-induced vasoconstriction and cyclic AMP content of the rabbit isolated femoral artery. 876 87

The beneficial effects of n-3 polyunsaturated fatty acids of fish oil in the prevention of fatal arrhythmias in myocardial ischemia were suggested to be at least in part mediated by a modulation of dihydropyridine-sensitive L-type calcium channels. As cardiac alpha 1-adrenoceptor stimulation has been suggested to have no significant effect on L-type calcium channels, the aim of this study using cultured neonatal rat cardiomyocytes was to investigate whether chronic n-3 polyunsaturated fatty acid exposure may have an influence on alpha 1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias. Pretreatment of the rat cardiomyocytes for 3 days in the presence of the n-3 polyunsaturated fish oil-derived fatty acid docosahexaenoic acid (60 mumol/l) markedly decreased alpha 1-adrenoceptor-stimulated increase in contraction velocity and induction of arrhythmias. The increase in contraction velocity of the cardiomyocytes induced by the beta-adrenoceptor agonist isoprenaline was also markedly reduced by the n-3 fatty acid pretreatment. Basal contractile amplitude and spontaneous beating frequency of the cardiomyocytes were not significantly altered by the docosahexaenoic acid exposure. The pretreatment of the rat cardiomyocytes for 3 days in the presence of docosahexaenoic acid (60 mumol/l) decreased alpha 1-adrenoceptor-stimulated formation of the calcium-mobilizing second messenger IP3 and its metabolites IP2 and IP1 by 55%. The depression of IP3 formation by docosahexaenoic acid treatment was not mediated by a decreased uptake of myo-inositol into the cardiomyocytes nor by a decreased synthesis of phosphatidylinositol bisphosphate (PIP2), the substrate of phospholipase C. The level of glycerol-3-phosphate, an important substrate of the phosphoinositide cycle, was unaltered by the docosahexaenoic acid pretreatment. Receptor binding studies revealed that the dissociation constant and maximal binding capacity of the alpha 1-adrenoceptor antagonist (3H)prazosin was unchanged by the n-3 polyunsaturated fatty acid exposure. Beta-Adrenoceptor-and forskolin-stimulated adenylyl cyclase activities were not diminished by the docosahexaenoic acid pretreatment. Chronic exposure of the cardiomyocytes to the n-6 polyunsaturated fatty acid arachidonic acid (60 mumol/l) did neither significantly alter alpha 1-adrenoceptor-induced inositol phosphate formation nor alpha 1-adrenoceptor-stimulated increase in contraction velocity. The results presented show that chronic n-3 polyunsaturated fatty acid pretreatment of rat cardiomyocytes leads to a marked impairment of alpha 1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias concomitant with a n-3 fatty acid-induced decrease in IP3 formation. This derangement of the phosphoinositide pathway by chronic n-3 fatty acid exposure may, thus, contribute to the beneficial effects of fish oil-derived fatty acids in the prevention of fatal arrhythmias in myocardial ischemia.
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PMID:Exposure to the n-3 polyunsaturated fatty acid docosahexaenoic acid impairs alpha 1-adrenoceptor-mediated contractile responses and inositol phosphate formation in rat cardiomyocytes. 885 87

Abnormalities of hypothalamus-pituitary-adrenal axis regulation are common in the elderly and excess glucocorticoids have been implicated in the loss of neural function in aging. In the current study, we examined cell signaling mediated through adenylyl cyclase in brain regions, heart and liver of young and aged rats given continuous infusions of dexamethasone (10 or 50 micrograms/kg/day) for 26 days. Aged control animals showed significant deficits in total adenylyl cyclase activity (assessed with forskolin-Mn++) in the brain regions and the heart; superimposed on this change, the striatum and the heart displayed interference with the response mediated either at the level of G-protein coupling to cyclase (striatum) or neurotransmitter receptor coupling to G-proteins (heart). Administration of dexamethasone to young rats did not reproduce the effects of aging on any of the measures of adenylyl cyclase, despite the fact that the higher dose produced Cushingoid effects. The same dexamethasone regimens given to aged rats produced alterations in G-protein coupling mechanisms in the cortex and in serotonergic-mediated cyclase responses in the striatum, and also decreased basal enzyme activity in the heart. In contrast to the brain regions and the heart, the liver showed unique effects of aging and dexamethasone. Total adenylyl cyclase activity, the enzymatic response to beta adrenergic stimulation and the number of beta adrenergic receptors were all elevated in aged animals as compared to the younger cohort. Dexamethasone decreased both hepatic beta receptor numbers and isoproterenol responsiveness in young animals, but increased receptor binding in aged animals. These data indicate that the defects associated with aging in the central nervous system and the cardiac cell signaling mediated through adenylyl cyclase are not a result of glucocorticoid excess; however, central and peripheral tissues respond differently to glucocorticoids in aged vs. young animals. Given the high incidence of hypothalamus-pituitary-adrenal axis dysregulation in the elderly, and particularly in elderly depression, effects of glucocorticoids on cell signaling may contribute to disruption of cell function and to hypo- or hyper-reactivity to drugs, such as antidepressants, that act by altering synaptic transmission.
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PMID:Aging and glucocorticoids: effects on cell signaling mediated through adenylyl cyclase. 893 Jan 49

The photoreceptor cells of the pike pineal organ transduce 24-h light/dark (LD) information to synchronize the clocks driving the melatonin (MEL) rhythm. In fish, the nocturnal rise in MEL synthesis is associated with an increase in cyclic adenosine 3', 5'-monophosphate (cAMP) production and with Ca2+ entry, through voltage-gated channels. Light induces inhibition of MEL synthesis and a depression of cAMP content, as well as closure of Ca2+ channels. Cyclic guanosine 3',5'-monophosphate (GMP) levels also are reduced upon acute illumination but this second messenger of phototransduction does not appear to be directly involved in the control of MEL metabolism. It is not known whether cAMP and/or cGMP are components of the clock machinery. In this study we measured cAMP and cGMP contents (static culture) and release (perifusion culture) using pike pineal organs maintained under LD or DD (constant darkness). Under LD, cAMP levels were low at noon and midnight, and high at dawn and dusk, in organs as well as in perfusates. This pattern was maintained under DD, with a major peak occurring at the beginning of subjective light, and a minor peak at the beginning of subjective darkness; only one peak during the subjective light was seen in the perfusates. Under DD, the MEL rhythm displays only one peak during the subjective night. It is suggested that increases in cAMP might not always be correlated with increases in MEL secretion. Under LD, variations in cGMP content were not statistically significant; however, in the perfusates, the levels were higher during the night than during the day. This suggests that: (1) extrusion participates in the regulation of intracellular levels of cGMP, (2) nocturnal synthesis of cGMP is higher than its catabolism, and (3) synthesis is increased during the day to compensate for the light-induced activation of catabolism. Under DD, the cGMP content and release were higher during the subjective night than during the subjective day, revealing a circadian component in the regulation of cGMP metabolism. This may provide the basis for the generation of membrane-related circadian events including variations in membrane potential, in the opening/closure of voltage-gated channels (e.g. Ca2+ channels), or in enzyme activities (adenylyl cyclase, cGMP-dependent phosphodiesterase).
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PMID:Variations in cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate content and efflux from the photosensitive pineal organ of the pike in culture. 906 50

Galanin, a neuroendocrine peptide with a multitude of functions, binds to and acts on specific G-protein coupled receptors. Only one galanin receptor subtype, GalRI, has been cloned so far, although pharmacological evidence suggests the presence of more than one galanin receptor subtype. These receptors mediate via different Gi/Go-proteins the inhibition of adenylyl cyclase, opening of K+-channels and closure of Ca2+-channels. Galanin inhibits secretion of insulin, acetylcholine, serotonin and noradrenaline, while it stimulates prolactin and growth hormone release. Determination of structural components of galanin receptors required for binding of the peptide ligand as carried out recently will facilitate the screening and design of molecules specifically acting on galaninergic systems with therapeutic potential in Alzheimer's disease, feeding disorders, pain and depression.
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PMID:Galanin receptors: involvement in feeding, pain, depression and Alzheimer's disease. 912 74


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