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)

Isolated guinea pig hearts were perfused with Krebs buffer in the absence or presence of 10 microM adenosine for 60 to 120 min followed by a 15 min washout with adenosine-free buffer. The effects of isoproterenol on left ventricular dP/dt and heart rate were then determined. Perfusion with adenosine for a minimum of 90 min followed by washout resulted in a 40% depression of the dose-response curve of left ventricular dP/dt to isoproterenol. This depressed inotropic responsiveness persisted for at least 1 hr after cessation of adenosine perfusion. The heart rate response to isoproterenol was unaffected. Also, adenosine perfusion had no effect on ouabain inotropism. Measurement of adenosine in coronary effluent and in ventricular tissue by radioimmunoassay verified that no residual elevated adenosine remained following perfusion and washout. Moreover, isoproterenol-induced release of adenosine into the coronary effluent did not differ between control and adenosine-treated hearts. Addition of 100 microM theophylline, an adenosine receptor antagonist, to the adenosine containing buffer during perfusion prevented the depressed response to isoproterenol. In membrane fractions prepared from ventricles, beta receptors were assessed by (-) [125] iodocyanopindolol binding and neither the density of these receptors nor their affinity for agonists or antagonists was altered by adenosine perfusion. However, activation of adenylate cyclase by isoproterenol (10 microm) was significantly depressed in membranes from adenosine perfused hearts. These findings are consistent with a receptor mediated action of adenosine to produce persistent depression of catecholamine inotropism. Such an effect may be important in heart failure where myocardial levels of adenosine are elevated and circulating levels of catecholamines are high.
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PMID:Persistent desensitization of the heart to the inotropic action of isoproterenol by adenosine. 260 56

Myocardial flow maldistribution and transmural steal phenomena, due to excessive arteriolar dilation elicited by elevated adenosine release during exercise, might be the mechanism of myocardial ischemia in patients with syndrome X. The effect of the adenosine receptor blocker aminophylline (AM) on effort ischemia in patients with syndrome X was tested: following double blind, randomized intravenous infusion of aminophylline (6 mg/kg over 15 minutes) or placebo, 8 patients with syndrome X underwent exercise stress test. After AM administration there was an increase in work tolerance (AM = 7.7 +/- 1.2 minutes of exercise vs placebo = 5.6 +/- 0.9, p less than 0.01) paralleled by an increase of the ischemic threshold, evaluated through the rate pressure product (mmHg x beats/min x 1/100) at 0.1 mV of ST-segment depression or at peak exercise (AM = 278 +/- 55 vs placebo = 230 +/- 24, p less than 0.05). AM prevented the occurrence of ischemic ECG signs in all 8 patients. Thus, at a dosage which effectively inhibits adenosine receptors, aminophylline infusion exerts beneficial effect on exercise induced ischemia in syndrome X, possibly through the prevention of transmural steal phenomena, elicited by inappropriate adenosine release during effort.
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PMID:[Increase in tolerance to physical effort in patients with X syndrome after acute administration of aminophylline]. 268 20

In the present study we have used the purine agonist R-phenylisopropyladenosine (PIA) which suppresses excitatory amino acid release to assess its effect on quinolinate toxicity. Quinolinic acid was injected into the rat hippocampus alone or with PIA and the animals allowed to recover. After 4 days the brain was removed for histological examination. The extent of neuronal degeneration was assessed blind by an independent observer on a scale of 0 (no damage) to 10 (complete degeneration). Co-administration of PIA protected against the toxicity, and this protective action of PIA was blocked by a xanthine adenosine receptor antagonist. However, systemic injections of PIA or the non-purine ganglion blocking drug trimetaphan, both of which caused significant depression of blood pressure, potentiated quinolinate toxicity. The results may indicate an interaction between endogenous excitotoxins and episodes of hypotension which may be critical in determining cell death in the CNS.
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PMID:Quinolinic acid neurotoxicity: protection by intracerebral phenylisopropyladenosine (PIA) and potentiation by hypotension. 277 Nov 65

The efficacy of the adenosine receptor blocker aminophylline on exercise capacity in patients with effort ischemia and documented coronary artery disease has been previously documented. In this study the effect of aminophylline on effort electrocardiographic (ECG) alterations and chest pain was tested in eight patients with syndrome X (anginal chest pain on effort, ischemic ECG changes during exercise, positive dipyridamole test, normal epicardial coronary arteries on angiography and absence of coronary spasm after ergonovine). After double-blind, randomized intravenous infusion of aminophylline (6 mg/kg body weight over 15 min) or placebo (20 ml of saline solution over 15 min), the eight patients with syndrome X underwent an upright bicycle exercise stress test on 2 consecutive days. After aminophylline, there was an increase in effort tolerance (aminophylline 7.7 +/- 1.2 min of exercise versus placebo 5.6 +/- 0.9, p less than 0.01) paralleled by an increase of the rate-pressure product (mm Hg x beats/min x 1/100) at 0.1 mV of ST segment depression or at peak exercise (aminophylline 278 +/- 55 versus placebo 230 +/- 24, p less than 0.05). Aminophylline provoked the abolition of ECG signs of ischemia in all eight patients. Thus, at a dosage that should effectively inhibit adenosine receptors, aminophylline infusion exerts a beneficial effect on exercise-induced chest pain and ischemia-like ECG changes in syndrome X. This effect occurs possibly through the prevention of myocardial flow maldistribution elicited by inappropriate adenosine release during effort in the presence of increased coronary resistance at the level of small intramural coronary arteries. This study, however, does not document the ischemic nature of effort-induced pain and ECG alterations in syndrome X.
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PMID:Improved exercise capacity with acute aminophylline administration in patients with syndrome X. 280 3

Exercise-induced ischemia is generally attributed to an increase in myocardial demand in the presence of coronary stenosis limiting flow supply. An additional mechanism--the occurrence of coronary steal due to excessive endogenous adenosine release--has also been hypothesized. The effect of adenosine receptor blocking by aminophylline in effort ischemia was tested in 8 patients with stable effort-induced angina pectoris, reproducible positive exercise stress tests and angiographically assessed coronary artery disease. Following double-blind, randomized intravenous infusion of aminophylline (3 mg/kg over 3 minutes) or placebo (20 ml of saline over 3 minutes), the patients underwent upright bicycle exercise stress tests on 2 consecutive days. After aminophylline, there was an increase in work tolerance (aminophylline 7.5 +/- 1.8 minutes of exercise vs placebo 5.4 +/- 1.5 minutes; p less than 0.05). There was a parallel increase in the ischemic threshold, evaluated with the rate-pressure product (mm Hg X beats/min X 100(-2)) at 0.1 mV of ST-segment depression (221 +/- 35 vs 184 +/- 20; p less than 0.01). Thus, at a dosage that should effectively inhibit adenosine receptors, aminophylline infusion exerts a beneficial effect on exercise-induced ischemia, possibly through the prevention of myocardial flow maldistribution elicited by excessive adenosine release during effort.
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PMID:Exercise capacity after acute aminophylline administration in angina pectoris. 290 50

The effect of the metabolically stable adenosine analog (-)-N6(R-phenyl-isopropyl)-adenosine (PIA) on the rate of spontaneous Purkinje cell firing was studied in anesthetized rats. In control animals, systemically administered PIA elicited only small and inconsistent changes in firing rate. However, in animals previously treated with DSP4 (50 mg/kg i.p.), which selectively lesions central noradrenergic afferents, or with the adrenergic antagonist sotalol (15 mg/kg), PIA elicited consistent decreases in firing rate. These effects were antagonized by the systemic administration of the adenosine receptor antagonist aminophylline (50-150 mumol/kg). Local administration of adenosine by pressure ejection caused a dose-dependent depression of Purkinje cell firing that was likewise inhibited by the methylxanthine. In DSP4 treated rats the depression of synaptic transmission by adenosine in rat hippocampus in vitro was unaltered, and theophylline did not cause any marked rise in Purkinje cell firing, suggesting that DSP4 does not sensitize neurons to the depressant effects of adenosine derivatives. PIA also caused a dose-dependent decrease in arterial blood pressure and a decrease in heart rate that was of equal magnitude in control and DSP4 treated rats. The results show that the central effects of systemically administered adenosine analogs are altered by procedures that disrupt the normal depressant effect of tonic noradrenergic input.
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PMID:Inhibition of Purkinje cell firing by systemic administration of phenylisopropyl adenosine: effect of central noradrenaline depletion by DSP4. 298 46

Chronic administration of caffeine to mice (1 mg/ml in drinking water X 14 d) led to a downward shift in the dose-response curve for the locomotor effects of caffeine. Caffeine was also less effective as an antagonist against (-)-(N6-phenylisopropyl)-adenosine (PIA)-induced analgesia in the tail flick assay in these animals. The dose-response curves of PIA for both analgesia and locomotor depression were shifted to the left in animals chronically administered caffeine. In mice chronically administered PIA (1 mg/kg/d X 14 d), the dose-response curves of PIA for both analgesia and locomotor depression were shifted to the right. The dose-response curve for the locomotor effects of caffeine was shifted to the left, and caffeine exhibited greater antagonist activity against the analgesic action of PIA in these animals. There was no change in the Kd or Bmax values of either 3H-PIA or 3H-diethylphenylxanthine (DPX, a potent adenosine receptor antagonist) in mice chronically administered PIA. The Bmax values for both 3H-PIA and 3H-DPX were significantly increased, while the Kd values were not changed in mice chronically administered caffeine. There was no detectable change in the brain levels of either PIA or caffeine in animals chronically treated with either drug. The results demonstrate that chronic administration of caffeine increases the sensitivity of mice to the actions of PIA and vice versa, providing supportive evidence for the interaction of these drugs at the same receptor, which is probably an adenosine receptor.
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PMID:Cross-tolerance studies between caffeine and (-)-N6-(phenylisopropyl)-adenosine (PIA) in mice. 300 86

The effects of Ro 15-1788, a benzodiazepine antagonist with some agonist properties, were studied on adenosine and adenosine 5'-N-ethyl-carboxamide (NECA)-evoked depressions of rat cerebral cortical neuronal activity. Iontophoretically applied Ro 15-1788 had both antagonistic and potentiative interactions with adenosine. Reductions in the magnitude of adenosine-evoked depressions of firing were evident during the period of Ro 15-1788 application, with a long-lasting potentiative effect becoming apparent upon termination of the Ro 15-1788 application. Depressions of cell firing evoked by NECA, an uptake-resistant analog of adenosine, were antagonized by Ro 15-1788, with no subsequent potentiation. Larger applications of Ro 15-1788 had a depressant action on neuronal firing, which was antagonized by caffeine (20 mg/kg), an adenosine receptor blocker. These results indicate that Ro 15-1788 may be an antagonist at the adenosine receptor as well as a potentiator of the adenosine response. The prolongation of the adenosine depression is likely to be the result of a persistent inhibition of adenosine uptake by Ro 15-1788. These diverse effects on the adenosine response may account for some of the complex behavioral actions of Ro 15-1788.
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PMID:Ro 15-1788 both antagonizes and potentiates adenosine-evoked depression of cerebral cortical neurons. 310 26

The effect of theophylline on the working capacity of patients with ischaemic heart disease was evaluated in a double-blind, randomized cross-over study. Eight patients, receiving no medication, with stable effort-provoked angina pectoris and typical exercise-induced ST depressions were studied. Following intravenous administration of theophylline or placebo, the patients did a supine leg exercise limited by intolerable chest pain. The workload was continuously increased by 10 W/min. Following theophylline treatment the workload at the onset of chest pain increased from 71 +/- 9 to 114 +/- 14 W (P less than 0.002). The ST depression was less pronounced following theophylline at submaximal exercise (-0.01 +/- 0.00 vs. -0.09 +/- 0.02 mV, P less than 0.005, at 70 W). The maximum tolerable workload increased from 129 +/- 15 after placebo infusion to 153 +/- 12 W after theophylline infusion P less than 0.01). It is speculated that this beneficial effect of the adenosine receptor antagonist theophylline may possibly be due to inhibition of a pathophysiological coronary steal induced by elevated levels of adenosine during ischaemia.
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PMID:Improved working capacity following theophylline infusion in patients with ischaemic heart disease. 319 60

Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors.
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PMID:Adenosine receptors: development of selective agonists and antagonists. 358 7


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