UMLS:C0011570 - FACTA Search

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)

CK-2289 is an inhibitor of type III cyclic 3'5'-adenosine monophosphate phosphodiesterase with potential utility in the treatment of congestive heart failure. We compared CK-2289 to milrinone and enoximone in several pharmacological models. Intravenous administration of CK-2289 to pentobarbital-anesthetized dogs (0.03 to 1 mg/kg) produced dose-related increases in myocardial dP/dTmax and decreased mean arterial blood pressure, similar to milrinone and enoximone. However, CK-2289 was 3-9 times more potent than either agent as a positive inotrope. Intraperitoneal and oral administration of CK-2289 and milrinone to mice produced central nervous system depression. Administered intravenously. CK-2289 and milrinone (1 mg/kg) inhibited, whereas enoximone (1 mg/kg) enhanced, guinea-pig gastric acid secretion. CK-2289 (0.01 to 0.3 mg/kg) and milrinone (0.03 to 1 mg/kg), given intravenously, did not affect neurotransmission to the rabbit sciatic nerve-gastrocnemius muscle preparation. Neither CK-2289 nor milrinone (100 microM) inhibited sympathetic neurotransmission, alpha 1-, muscarinic and thromboxane receptors. Both compounds relaxed canine arteries and veins. CK-2289 was devoid of effects on non-vascular smooth muscles of guinea-pig vas deferens and uteri and rabbit bronchi. CK-2289 (1 to 100 microM), milrinone and enoximone inhibited human platelet aggregation produced by adenosine diphosphate and sodium arachidonate. These data suggest that CK-2289 should be devoid of adverse renal, neural, smooth or skeletal muscle or gastrointestinal side effects associated with milrinone and enoximone therapy.
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PMID:Pharmacological comparison of CK-2289, an inodilator agent, with milrinone and enoximone. 165 60

Proceeding from recent evidence about the mechanism of action of lithium and of the novel antidepressant rolipram, it is proposed that functional disturbances in intraneuronal signal transmission distal to the receptors of classic neurotransmitters (first messengers) play a role in the etiology of affective disorders. The second-messenger dysbalance hypothesis suggests that affective disorders are caused by the functional dysbalance of the two major intraneuronal signal-amplification systems (the adenylate-cyclase and the phospholipase-C system), with depression resulting from hypofunction of cyclic adenosine-3',5'-monophosphate-mediated effector cell responses together with an absolute or relative dominance of the inositoltriphosphate/diacylglycerol-mediated responses, and mania resulting from the converse. The usefulness of this hypothesis is discussed with respect to (a) the mechanism of action of current therapeutics and (b) the development of novel therapeutic approaches.
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PMID:The second-messenger dysbalance hypothesis of affective disorders. 217 71

The neurokinins, physalaemin, substance P, neurokinin A and bradykinin, were tested on the responses of single spinal neurons to the purines, adenosine 5'-triphosphate (ATP) and adenosine 5'-monophosphate and to GABA. Experiments were done on anaesthetized cats, recording extracellularly from functionally identified sensory neurons in the lumbar dorsal horn. All compounds were administered by iontophoresis. Neurokinins caused a slow, prolonged excitation which outlasted the period of application. Physalaemin was tested on responses to ATP in 24 units. In each case application of ATP caused either depression, excitation or a biphasic response when the application was not pre-conditioned by ejection of physalaemin. For 11 units, with ATP applications subthreshold to alter the on-going firing rate, such applications caused depression when they were preceded by administration of physalaemin. Three units were tested with ATP applications which caused the excitatory response; when the applications of ATP were preceded by ejection of physalaemin, there was then a depressant component in the response. In these 14 cases, the magnitude of the depression or of the depressant component of the response, was measured using currents which failed to produce depression in the absence of physalaemin ejection; the mean magnitude of this depression was 34.7 +/- 1.6% (+/- S.E.M.). With the 10 remaining units, responses to ATP were unaffected by application of physalaemin. The early components of the biphasic and excitatory responses were unaffected by physalaemin and hence it appeared to have a differential effect, enhancing only the depressant effects of ATP. The enhancement of depression was reversible, lasting up to 30 min following a single ejection. Neither control current nor glutamate mimicked the effect of physalaemin in the responses to application of ATP. The depressant response to adenosine 5'-monophosphate was also enhanced by physalaemin: ejections of adenosine 5'-monophosphate subthreshold to affect the on-going firing rate caused depression after physalaemin application in 3 of 8 units (average depression: 35.0 +/- 3.3%). On the other hand, depression induced by GABA was unaffected by physalaemin in every case (n = 8); in 4 of these cases GABA was tested on units for which purine-induced depression was enhanced by physalaemin. Thus, physalaemin preferentially affected depressant responses to ATP and to adenosine 5'-monophosphate.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Purine-induced depression of dorsal horn neurons in the cat spinal cord: enhancement by tachykinins. 244 38

The present study was initiated to test to what extent preovulatory follicles are dependent on oxygen supply for maintaining their response to luteinizing hormone (LH). Female rats of the Sprague-Dawley strain were injected with 6 IU of pregnant mare serum gonadotropin (PMSG) on their 26th day of life. For in vitro experiments rats were killed 48-52 h after PMSG injection. Preovulatory follicles were dissected free, pre-incubated for 30 min and then incubated for 3 h without or with luteinizing hormone (LH, 1 microgram ml-1 medium) under different oxygen tensions in the gas phase (100, 13, 6 and 0 kPa). After incubation the accumulation of progesterone, cyclic-3',5'-adenosine monophosphate (cyclic AMP) and lactic acid were measured in the incubation media. Follicular adenosine-5'-triphosphate (ATP) content was measured in vivo (48-60 h after PMSG injection) immediately after isolation as well as after the incubation. Follicles isolated in vivo, during and after the ovulatory endogenous gonadotropin surge showed a depression in follicular ATP levels compared with levels before, suggesting that gonadotropins stimulate the follicle on the expense of ATP levels during the course of the preovulatory day. During a step-wise decrease of oxygen tension in vitro the preovulatory follicle maintained its response to LH as measured by progesterone and cyclic AMP accumulation. The preovulatory follicle could apparently compensate by increasing glycolysis, as measured by an increase in lactic acid accumulation. Tissue ATP levels were during these conditions maintained.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxygen dependency of preovulatory follicles from pregnant mare serum gonadotropin-treated immature rats. 282 Jan 96

Acetylcholine (ACh) in low doses (0.1-1 microM) reversibly inhibits voltage-dependent activation of the "pacemaker" current, if, in isolated sino-atrial node cells. This action is brought about by a negatively-directed shift of the current activation curve, opposite to that due to catecholamines on the same current. The if inhibition is antagonized by atropine, indicating the involvement of muscarinic receptors. In cells incubated in pertussis toxin-containing solutions, if does not respond to ACh, suggesting that G-proteins mediate the ACh-induced if depression. Further, ACh can inhibit if following catecholamine-induced stimulation, but has a negligible effect on if stimulated by forskolin, a direct activator of adenylate-cyclase. Our results indicate that ACh acts on if by inhibiting basal adenylate-cyclase activity.
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PMID:Acetylcholine inhibits activation of the cardiac hyperpolarizing-activated current, if. 282 12

Control of glycolysis during anoxia was investigated in five organs (heart, brain, liver, and red and white skeletal muscles) of the freshwater turtle, Pseudemys scripta, after 1 or 5 h of submergence in N2-bubbled water. Lactate was produced as the metabolic end product, with distinct organ differences in the amount (net lactate accumulation was 2.4-fold higher in brain than white muscle) and rate (lactate production in liver dropped 16-fold after the 1st h) of lactate accumulation. ATP and total adenylate contents of all organs were reduced (by 15-32%) after 1 h of submergence, but energy charge was maintained; after 5 h, adenylate contents had fully recovered. Changes in the levels of hexose and triose phosphate intermediates of glycolysis indicated an activation of glycolysis within the 1st h of anoxia exposure in brain, heart, and skeletal muscles. By 5 h, however, these were reversed, and a glycolytic rate depression was indicated, consistent with the overall metabolic rate depression accompanying long-term anaerobiosis in the turtle. Crossover analysis indicated glycolytic control at the pyruvate kinase reaction in all organs during both glycolytic activation and metabolic depression; regulatory control at the phosphofructokinase locus was primarily important only during glycolytic activation in heart and red muscle. The same analysis indicated a very rapid glycolytic inhibition in liver occurring within the 1st h of anoxia exposure; this allows glycogenolysis to be directed toward glucose export yielding the fermentative fuel used by other organs during anoxia.
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PMID:Organ-specific control of glycolysis in anoxic turtles. 297 50

A study was done of the effects of iontophoretic application of adenosine 5'-monophosphate (AMP) and adenosine 5'-triphosphate (ATP) on functionally identified neurones in the spinal dorsal horn of the cat. AMP depressed nearly two-thirds of the 32 neurones tested regardless of functional type; the remainder were unaffected. ATP, on the other hand, had three types of effect: depression, excitation and a biphasic effect which consisted of excitation followed by depression. A significant difference was found when a comparison was made of the frequency of occurrence of each of these three types of effect in the samples of non-nociceptive (n = 18) and of wide dynamic range neurones (n = 42): of non-nociceptive neurones 61% were excited, 11% were depressed, 6% had a biphasic response and 22% were unaffected; of wide dynamic range neurones 45% had a biphasic response, 19% were depressed, 14% were excited and 21% were unaffected (chi 2 = 16.2, P less than 0.005). The depressant effects of both AMP and ATP and the depressant phase of the biphasic effect of ATP seem to be mediated through activation of P1-purinergic receptors because these effects were blocked by theophylline, a P1-purinergic antagonist [Burnstock (1978) In Cell Membrane Receptors for Drugs and Hormones: A Multidisciplinary Approach, pp. 107-118]. Thus the biphasic effect appears to consist of excitatory and depressant responses in the same neurone. The differential effects of ATP on non-nociceptive vs wide dynamic-range neurones are similar to the differential effects on these neurones observed during activation of low-threshold primary afferents. This similarity, together with evidence that ATP can be released from primary afferent neurones [Holton and Holton (1954) J. Physiol., Lond. 126, 124-140; Holton (1959) J. Physiol., Lond. 145, 494-504], prompts us to suggest that ATP may be a chemical mediator of effects of low-threshold primary afferent inputs in the spinal dorsal horn.
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PMID:Effects of adenosine 5'-monophosphate and adenosine 5'-triphosphate on functionally identified units in the cat spinal dorsal horn. Evidence for a differential effect of adenosine 5'-triphosphate on nociceptive vs non-nociceptive units. 299 43

The delta Gp/delta mu H ratio has been measured in mitochondria close to state 4 in the presence of various uncoupler or K+/valinomycin concentrations in media containing either 1 mM or 50 mM Pi. Care has been taken to control the factors affecting delta Gp and delta mu H which could lead to an artefactual increase of the delta Gp/delta mu H ratio above the highest accepted value for the H+/ATP stoichiometry (n = 4, synthesis + transport). In particular, to avoid overestimation of delta Gp due to inactivation of the ATPases at low delta mu H or to the presence of adenylate kinase, the static head state was approached from the side of net ATP synthesis and delta Gp was measured in a state close to static head but still maintaining a residual rate of aerobic phosphorylation. For each concentration of uncoupler or K+, the Pi concentration and/or the adenylate energy charge (EC) as a function of time have been measured as indicators of net ATP synthesis. Only the values of delta Gp measured during a decrease in Pi concentration and/or an increase in EC have been considered to be meaningful for calculations of delta Gp/delta mu H ratios. Both uncouplers and K+ transport cause a marked depression of delta mu H and a parallel depression of the rate of ATP synthesis. However the low rate of ATP synthesis taking place under conditions of low delta mu H eventually results, especially at high Pi concentrations, in a relatively large delta Gp. The delta Gp/delta mu H ratios obtained at the lower delta mu H values exceed 4 and approach 6. Although slightly higher delta Gp/delta mu H ratios are obtained with valinomycin-treated than with uncoupler-treated mitochondria, the pattern of the rise of the force ratio as delta mu H decreases is similar in both cases. An increase of the delta Gp/delta mu H ratio above 4, the maximal accepted H+/ATP stoichiometry is thermodynamically incompatible with the delocalized protonic coupling model.
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PMID:Free energy coupling between H+-generating and H+-consuming pumps. Ratio between output and input forces. 300 29

1. Ouabain given by intracerebroventricular injection to mice in small doses (0.1-0.4 mug) produced a dose related depression of central nervous activity, characterized by a reduction in spontaneous locomotor activity, hypothermia, catalepsy and ptosis, lowered body posture and lack of response to external stimuli. Doses above 0.4 mug were excitatory, convulsant and lethal.2. The depressant effects could be antagonized by (+)-amphetamine, desmethylimipramine, dibutyryl cyclic 3'5'-adenosine monophosphate and caffeine.3. The MAO inhibitor nialamide produced only a small antagonism of ouabain, resulting in a greater rate of recovery from the depressant effects of ouabain.4. The depressant effects were associated with a marked elevation of whole-brain dopamine levels with little change in noradrenaline or 5-hydroxytryptamine.5. The dopamine-beta-hydroxylase inhibitor sodium diethyldithiocarbamate, administered by intracerebroventricular injection, produced effects qualitatively similar to those seen after ouabain.6. An interference with central transmitter function is postulated as a possible mode of action of intracerebroventricularly injected ouabain.
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PMID:Pharmacological properties of centrally administered ouabain and their modification by other drugs. 432 23

The metabolism of adenosine 3',5'-monophosphate (cyclic AMP) was studied in specific pathogen-free mice exposed to neonatal infection with mouse enterovirus or to malnutrition during early life. Metabolic activity was determined by measuring the turnover of cyclic AMP-8-(14)C to respiratory (14)CO(2), its incorporation into various organs and plasma, and the binding activity of synaptosome for cyclic AMP. Early malnutrition increased the catabolism of cyclic AMP as measured by expiration in respiratory CO(2). The level of cyclic AMP was lower in plasma and its incorporation into various tissues was decreased in infected and malnourished animals. Metabolic products of cyclic AMP were isolated from plasma by ion exchange chromatography. Cyclic AMP-8-(14)C had completely disappeared 9 hr after injection. Fewer metabolites of cyclic AMP were detected in infected or malnourished groups than in controls and the metabolic reaction from 5'-AMP to adenosine seemed to be slow in these animals. The ability to incorporate cyclic AMP to synaptosome was also impaired in the experimental groups. The concentrations of brain cyclic AMP were lower in infected or malnourished animals than in controls. Depression of accumulation of cyclic AMP probably resulted from excessive activity of phosphodiesterase, rather than from impairment of adenyl cyclase. Intraperitoneal administration of theophylline brought the activity level of phosphodiesterase to normal in infected or malnourished mice; this fact probably accounted for enhanced accumulation of brain cyclic AMP.
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PMID:Lasting biological effects of early environmental influences. VII. Metabolism of adenosine in mice exposed to early environmental stress. 433 97

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