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

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

Continued exposure of many beta-adrenoceptor-coupled adenylate cyclase systems to high doses of agonist causes diminished responsiveness, a phenomenon called desensitization. After exposure of isolated guinea pig tracheae to a high concentration of isoproterenol for 30 min, relaxation produced by subsequent challenge by a lower concentration was attenuated, as expected. However, potentiation of isoproterenol-induced relaxation by aminophylline was greater after desensitization as compared to that prior to desensitization. This observation was further investigated using a graphical method that allows quantitative and statistical evaluation of combinations of synergistically acting drugs. Concentration-relaxation curves (CRC) for isoproterenol alone and in the presence of a fixed concentration of aminophylline were determined in isolated rat trachea. A theoretical additive curve was constructed from the data obtained, and the displacement of the isoproterenol CRC from the theoretical additive curve caused by aminophylline in tracheae desensitized by 2.5 hr of exposure to 2 X 10(-5) M isoproterenol (DESN) was compared to that in tracheae equilibrated for a similar period in physiologic salt solution (CON). Desensitization had no significant effect on aminophylline-induced relaxation but caused a marked depression and right-shift of the isoproterenol CRC. In the CON group aminophylline shifted the isoproterenol CRC upward and to the left indicating that the synergistic interaction between the two agents was greater than additive. The left-shift and elevation of the ceiling effect of the isoproterenol CRC caused by aminophylline were significantly greater in the DESN group vs the CON group. These observations from intact tissue are compared with published data from biochemical and broken cell studies. The possibility of increased phosphodiesterase activity as an explanation for the observations reported is discussed.
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PMID:Potentiation of isoproterenol-induced relaxation of isolated trachea by aminophylline: modulation by desensitization. 361 5

Adenylate cyclase activity of the washed particles from the ventricles of rats made hypothyroid by propylthiouracil (P.T.U.) treatment was studied in the absence or presence of different concentrations of catecholamines, guanylimido-diphosphate (GppNHp) and NaF. The washed particles preparation of hypothyroid rat displayed higher basal adenylate cyclase activity in comparison to that in the euthyroid animal. Fluoride stimulation was unaltered but GppNHp stimulation was markedly depressed over a wide range of concentrations in the hypothyroid heart washed particles. Epinephrine stimulation in the presence of GppNHp was altered only at 10(-5) to 10(-4)M concentrations. Depressed responsiveness of cardiac adenylate cyclase to GppNHp and epinephrine was also found in washed particles of thyroidectomized rats. Depression of GppNHp or epinephrine response in hypothyroid animals was reversed 48 hours after T3 administration. In contrast to the washed particulate preparation, no depressions in the responses of adenylate cyclase to GppNHp or epinephrine were seen in the purified sarcolemmal membranes from P.T.U. induced hypothyroid or thyroidectomized rat hearts. It is proposed that altered guanine nucleotide binding or altered guanine nucleotide binding protein-catalytic subunit interaction in the adenylate cyclase system may be an underlying mechanism of depressed positive inotropic action of catecholamines in the hypothyroid state.
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PMID:Alterations in the cardiac adenylate cyclase activity in hypothyroid rat. 385 Jul 75

Forskolin, a potent activator of adenylate cyclase, and isoprenaline, an unselective beta-adrenoceptor agonist, were studied in vitro on tissues from guinea-pig with respect to relaxation of the carbachol-contracted trachea, increase in the force of contraction of the papillary muscle and depression of subtetanic contractions of the soleus muscle, three well-characterized beta-adrenoceptor-mediated effects. Forskolin and isoprenaline relaxed the trachea and increased the force of contraction of the papillary muscle. Isoprenaline but not forskolin caused a depression of the subtetanic contraction of the soleus muscle. Forskolin did not seem to potentiate the effects of isoprenaline on the tissues studied; the combined effects appeared to be a mere addition. Forskolin did not increase the efficacy of the partial agonist prenalterol either. It is concluded that there is no simple relation between c-AMP generation and the functional response to beta-adrenoceptor agonists. Forskolin should not be used uncritically to probe beta-adrenoceptor-mediated effects.
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PMID:Comparison of the effects of forskolin and isoprenaline on tracheal, cardiac and skeletal muscles from guinea-pig. 404 Apr 70

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

1 The selectivity of alpha-adrenoceptors mediating the pro-aggregatory response of human and rabbit platelets to adrenaline and the conditions required to permit expression of an aggregatory response to partial agonists at these alpha-adrenoceptors have been studied.2 Yohimbine causes effective blockade of the pro-aggregatory responses whereas indoramin and prazosin are ineffective.3 The clonidine analogue, UK-14304, is nearly as effective as adrenaline in inducing an aggregatory response in human platelets and a pro-aggregatory response in rabbit platelets. Cross-tachyphylaxis between adrenaline and UK-14304 has been demonstrated.4 Clonidine is a weak agonist for the pro-aggregatory response of rabbit platelets and in some donors for the aggregatory response of human platelets.5 Methoxamine induces a pro-aggregatory response in human platelets which is blocked by indoramin or prazosin but not by yohimbine. No such response to methoxamine is observed in rabbit platelets.6 The divalent cation ionophore, A-23187, induces an aggregatory response to clonidine (in platelets from a non-responsive donor), phenylephrine and methoxamine in human platelets and to adrenaline, UK-14304 and clonidine in rabbit platelets. A secretory response to clonidine is also induced by A-23187 in human platelets.7 The adenylate cyclase inhibitor, SQ-22536, is ineffective in either inducing a response to the alpha-agonists or potentiating the effect of A-23187.8 The aggregatory responses to adrenaline and UK-14304 in rabbit platelets and to clonidine in human and rabbit platelets, which can be induced by A-23187, are blocked by yohimbine but not by prazosin or indoramin.9 From these studies we conclude that the pro-aggregatory responses of human and rabbit platelets to adrenaline are mediated primarily by alpha(2)-adrenoceptors. The presence of alpha(1)-adrenoceptors on human platelets is confirmed but these receptors do not appear to be present on rabbit platelets. The conditions required for expression of an aggregatory response to partial agonists at the human and rabbit platelet alpha-adrenoceptors implicate an increase in cytosolic Ca(2+) concentration as a key event in stimulus-response coupling but do not indicate such a role for depression of cyclic adenosine-3',5'-monophosphate concentration.
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PMID:Interaction of selective alpha-adrenoceptor agonists and antagonists with human and rabbit blood platelets. 611 Apr 51

1. Isolated rat heart sarcolemma was treated with different concentrations of an ionic detergent, deoxycholate (DOC) and ATP hydrolysis in the presence of Ca2+ or Mg2+ was determined. 2. Both Ca2+-dependent ATPase and Mg2+-dependent ATPase activities were decreased in the DOC-treated membranes; however, the depression of Mg2+-dependent ATPase activity was greater than that of Ca2+-dependent ATPase. 3. The differential changes in Ca2+-dependent ATPase and Mg2+-dependent ATPase activities were apparent when incubations with DOC were carried out for different time intervals and at different temperatures. 4. In DOC-treated preparations, the Km value for Ca2+-dependent ATPase was decreased whereas that for Mg2+-dependent ATPase was increased. The half maximal velocities of the Ca2+-dependent ATPase and Mg2+-dependent ATPase enzyme reactions in the treated preparations were obtained at a DOC: membrane protein ratio of 3.0 and 0.6, respectively. 5. In the DOC-treated membranes exhibiting the half maximal velocities of enzyme reactions, the Ka value for Ca2+-dependent ATPase was drastically reduced but remained unchanged for Mg2+-dependent ATPase. 6. The DOC treatment was associated with a loss of protein as well phospholipids and resulted in changes in the ultrastructural integrity of the membrane. 7. Varying degrees of decreases in the activities of sarcolemmal adenylate cyclase. (Na+-K+)-ATPase, 5'-nucleotidase and calcium binding were seen upon DOC treatment. 8. The extent of reduction in Ca2+-dependent ATPase and Mg2+-dependent ATPase activities were also different when the membrane was treated with a non-ionic detergent, Lubrol PX. 9. These data suggest that Ca2+-dependent ATPase in heart sarcolemma is more resistant than Mg2+-dependent ATPase to detergent treatments and further indicate some differences in the properties of these enzymes.
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PMID:Ca2+- and Mg2+-dependent ATPase activities in the deoxycholate-treated rat heart sarcolemma. 612 55

Rats fed a diet deficient in both vitamin D and Ca2+ exhibited a greater depression of the renal parathyroid hormone (PTH)-dependent adenylate cyclase than was observed in rats fed diets deficient in either vitamin D or calcium. Total serum Ca2+ was decreased from a control level of 11.2 mg/dl to 8.5 mg/dl in rats fed the diet deficient in calcium alone, and to 5.4 mg/dl in rats fed the diet deficient in vitamin D. Serum calcium was decreased further to 4.3 mg/dl in rats fed the diet deficient in both vitamin D and Ca2+. Serum immuno-reactive PTH was significantly elevated over control levels when rats were fed the test diets; however, there were no significant differences between the elevated levels in the three experimental groups. Repletion of rats deficient in vitamin D only with a single oral dose of 3200 I.U. vitamin D-2 resulted in restoration of serum calcium to normal levels, a return of serum PTH to the control state, and an associated increase in PTH-dependent adenylate cyclase activity to the control level by 72 h. Repletion of rats deficient in both vitamin D and Ca2+ with the same dose of vitamin D-2 raised serum Ca2+ to 7.2 mg/dl by 72 h, but did not cause a reduction in circulating PTH, nor did it result in any significant improvement in the responsiveness of the membrane adenylate cyclase to PTH. These results suggest that elevated PTH is a factor in the down regulation of the PTH-dependent adenylate cyclase, but do not rule out a role for calcium as a regulatory factor.
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PMID:Renal parathyroid hormone-dependent adenylate cyclase activity after repletion of vitamin D-deficient rats with vitamin D-2. 625 4

1 RMI 12330A, a lactam-imine, at concentrations of 10(-4) M and higher, inhibited basal as well as isoprenaline and NaF-stimulated adenylate cyclase activity of guinea-pig heart homogenates. However, RMI 12330A was a more potent inhibitor of histamine-stimulated adenylate cyclase (IC50 of 1.5 X 10(-5) M). 2 In the isolated work-performing heart of the guinea-pig, RMI 12330A (IC50 of 1.1 X 10(-6) M) depressed all cardiac functions: pressures developed, dP/dt, contractile force, dF/dt, work performance and stroke work. Left atrial pressure rose and the positive inotropic response to increasing heart rate (staircase) became negative. Histamine, isoprenaline and ouabain no longer caused positive inotropic effects. 3 Increasing the perfusate calcium concentration from 2.5 mM to 4.5 and 6.5 mM completely restored cardiac function after its depression by RMI 12330A. 4 RMI 12330A uncoupled mitochondrial oxidative phosphorylation; the classical uncoupler, dinitrophenol, had the same effects on cardiac dynamics as RMI 12330A. 5 RMI in high doses inhibited hydrolytic activity of Na+, K+-ATPase of crude and purified heart preparations (IC50 of 1.7 X 10(-4) M) and inhibited ouabain binding to the same enzymes (IC50 of 1.5 X 10(-4) M). 6 A lactam-imine analogue of RMI 12330A that had no effect on adenylate cyclase, was also without effect on any of the systems examined.
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PMID:Effects of RMI 12330A, a new inhibitor of adenylate cyclase on myocardial function and subcellular activity. 625 99

The myocardial responsiveness of conscious, instrumental dogs to exogenously administered isoproterenol and norepinephrine was investigated in neonatal, 6-wk-old, and adult animals. Comparable base-line values for peak left ventricular derivative of pressure with respect to time were observed in all age categories. However, when compared with adult responses, the sympathomimetic amine-induced increases in neonatal left ventricular dP/dt were significantly blunted at each concentration of adrenergic agonist examined, whereas the 6-wk-old puppies displayed an intermediate inotropic response. To investigate the cellular mechanisms of this blunted neonatal response, we correlated physiologic and biochemical measurements of the myocardial responses to catecholamines in each age category. When compared with adult myocardial membrane preparations, neonatal cardiac membranes were characterized in vitro by an increased density of beta-adrenergic binding sites, comparable affinity for adrenergic agonists and antagonists, and an enhanced coupling of adenylate cyclase activation to receptor occupancy. Simultaneous changes in either the serum catecholamine concentration or the membrane content of other intrinsic proteins failed to account for the observed neonatal increase in beta-adrenergic receptor density. These findings are most consistent with a compensatory mechanism of the cardiac cell membrane, whereby an inherent depression in the adrenergic responsiveness of the immature myocardium appears to induce the increase in receptor density and activation of adenylate cyclase.
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PMID:Cellular mechanisms of impaired adrenergic responsiveness in neonatal dogs. 625 59


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