Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cocaine can induce lethal cardiovascular events, including myocardial infarction and ventricular fibrillation. The mechanisms responsible for these cardiotoxic effects of cocaine remain largely to be determined. Cocaine has both sympathomimetic (inhibition of neuronal uptake of norepinephrine) and local anesthetic (Na+ channel blockade) properties. Neurotransmitters released from cardiac sympathetic nerves bind to both alpha- and beta-adrenergic receptors eliciting a cascade of intracellular responses. Stimulation of beta-adrenergic receptors activates adenylate cyclase, increasing cyclic AMP levels, whereas alpha-adrenergic receptor stimulation activates phospholipase C, increasing inositol trisphosphate. These second messengers, in turn, elicit increases in cystolic calcium. Elevations in cystolic calcium can provoke oscillatory depolarizations of the cardiac membrane, triggering sustained action potential generation and extrasystoles. Cocaine also acts as a local anesthetic by inhibiting sodium influx into cardiac cells, which impairs impulse conduction and creates an ideal substrate for reentrant circuits. Thus, the adrenergic and anesthetic properties of cocaine could act synergistically to elicit and maintain ventricular fibrillation. Adrenergic receptor activation would trigger the event whereas sodium channel blockade would create the reentrant substrate to perpetuate the malignant arrhythmias.
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PMID:Mechanisms responsible for the cardiotoxic effects of cocaine. 218 73

Prolonged treatment of cultured rat heart muscle cells containing beta 1- and non-muscle cells containing beta 2-adrenoceptors with beta-adrenoceptor antagonists devoid of intrinsic sympathomimetic activity had no effect on beta-adrenoceptor density. In contrast, antagonists with intrinsic sympathomimetic activity decreased beta-adrenoceptor density and response (adenylate cyclase stimulation) in both heart muscle (beta 1) and non-muscle cells (beta 2) by a maximum of about 50%. An even larger down-regulation of beta-adrenoceptors and loss of receptor-stimulated adenylate cyclase activity was induced by the full endogenous agonist, noradrenaline, with the beta-adrenoceptors of heart muscle cells (beta 1) being much more sensitive to the beta 1-selective noradrenaline than the heart non-muscle cell beta 2-adrenoceptors. When combined with noradrenaline, the antagonists with intrinsic sympathomimetic activity prevented the action of noradrenaline at both beta 1- and beta 2-adrenoceptors, thereby leading to an apparent up-regulation of receptor density and response. This apparent reversal from an agonist to an antagonist action was observed at much lower concentrations of noradrenaline at beta 1- than at beta 2-adrenoceptors. The data presented indicate that the beta-adrenoceptor antagonists with intrinsic sympathomimetic activity, but not those without, upon prolonged treatment decrease the density and responsiveness of both beta 1- and beta 2-adrenoceptors in cultured rat heart cells. This suggests that the intrinsic sympathomimetic activity of these agents is not a subtype-selective component. Furthermore, the agonist and antagonist activity of these agents apparently depends on the concomitant presence of an endogenous full agonist and an its own affinity and that of the partial agonist for the beta-adrenoceptor subtype.
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PMID:Intrinsic sympathomimetic activity of beta-adrenoceptor antagonists: down-regulation of cardiac beta 1- and beta 2-adrenoceptors. 257 97

Pirbuterol and nylidrin, both purported sympathomimetic amines, reduced intraocular pressure (IOP) when given topically (50 microliter, 0.1%) to albino rabbits. Pirbuterol increased the cyclic-AMP concentration in aqueous humor by a factor of 3.25, while nylidrin had no effect on aqueous cyclic-AMP nor on adenylate cyclase activity of iris-ciliary body membranes assayed in vitro. Studies of the receptor affinity of pirbuterol, timolol and nylidrin were carried out on iris-ciliary body membranes by competition binding with radioactive ligands. Four ligands were used that appear to label separate subpopulations of adrenergic receptors; dihydroalprenolol (beta-receptors), WB-4101 (alpha 1-receptors) prazosin (alpha 1-receptor subpopulation) and yohimbine (alpha 2-receptors). Pirbuterol and timolol showed exclusive selectivity for beta-receptors with high affinities (Kd 12.6 and 0.48 nM, respectively) compared with other adrenergic receptor populations in iris-ciliary body. Nylidrin had high affinities for beta-receptors (Kd 22 nM) and for the subpopulation of alpha 1-receptors labelled by prazosin (Kd 6.5 nM), but showed 100-fold lower affinity and complex binding characteristics to the two other classes of alpha-adrenergic receptor sites labelled by WB-4101 and yohimbine, respectively. The results show that pirbuterol and timolol are highly beta-receptor selective and that hypotensive responses to these drugs are not mediated by the other classes of alpha-adrenergic receptor determined in this study. However, the hypotensive response to nylidrin may be related to its prazosin-like (alpha 1-receptor) antagonist properties with additional activity at beta-receptors.
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PMID:Ocular hypotension in the rabbit. Receptor mechanisms of pirbuterol and nylidrin. 285 89

The thermodynamic parameters associated with the interactions of agonists and antagonists with digitonin-solubilized beta adrenergic receptors were determined. A rapid method for measuring the binding of [125I]iodopindolol to soluble receptors using glass-fiber filters was developed. The binding of [125I]iodopindolol, an antagonist with intrinsic sympathomimetic activity, to soluble receptors was temperature-sensitive as is the binding of the ligand to membrane-bound receptors. The interactions of propranolol and timolol with soluble receptors were independent of temperature. In contrast, the binding of agonists to soluble receptors was sensitive to temperature, although insensitive to GTP. Thermodynamically, the interactions of the antagonists timolol and propranolol with soluble beta adrenergic receptors were entropy-driven, with little contribution from changes in enthalpy. This is consistent with a hydrophobic interaction between the receptor and the antagonist. The binding of [125I]iodopindolol was enthalpy-driven. The binding of full agonists with soluble receptors was described thermodynamically by changes in enthalpy and entropy that were negative relative to the values for propranolol and timolol, suggesting that the guanine nucleotide-binding protein required for stimulation of adenylate cyclase activity and an intact lipid environment are not involved in the thermodynamics of formation of the low-affinity component of agonist binding. These results are consistent with an agonist-induced change in the conformation of the receptor.
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PMID:Thermodynamic properties of agonist interactions with the beta adrenergic receptor-coupled adenylate cyclase system. II. Agonist binding to soluble beta adrenergic receptors. 287 Jan 75

The extent of stimulation of the enzyme adenylate cyclase, and the concomitant production of cAMP, by a number of beta-adrenoceptor agonists, all belonging to the class of the N-tert-butylphenylethanolamines, has been determined. The results have been used as direct measures for intrinsic sympathomimetic activity (ISA) and were correlated with various physicochemical parameters of the compounds. Significant correlations were established by means of the method of multiple regression analysis, and it was demonstrated that electronic effects only govern ISA. The use of 13C NMR chemical shifts of the aromatic C atoms proved to be a valuable tool in this analysis.
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PMID:Quantitative evaluation of the beta 2-adrenoceptor intrinsic activity of N-tert-butylphenylethanolamines. 287 Jan 89

Nine different beta-adrenoceptor antagonists (BAA), five with intrinsic sympathomimetic activity (ISA), were examined for their ability to inhibit isoproterenol-stimulated adenylate cyclase (AC) activity and specific 125I-cyanopindolol (CYP) binding in crude membrane particles from human myocardium. The BAA's were: propranolol, pindolol, timolol, alprenolol, metoprolol, atenolol, prenalterol, ICI 141.292 'Visacor', and ICI 118.587 'Corwin'. Whether BAAs with strong ISA were able to stimulate AC activity by themselves were examined in separate experiments and compared to the AC stimulation by full agonists. All the BAAs caused a concentration dependent, and at high doses apparently complete, inhibition of both isoproterenol-stimulated AC activity and 125I-CYP binding. Both assays made possible a 'potency-ranking' of the different BAAs (pindolol greater than or equal to propranolol and timolol greater than ICI 142.292 and alprenolol greater than ICI 118.587, prenalterol and metoprolol greater than atenolol). Corrected IC50-values, derived from inhibition curves with both techniques, show that receptor binding and inhibition of receptor function follow each other closely. Prenalterol caused a very weak AC activation (5.4% of maximum), whereas the 'ISA-blockers', pindolol, ICI 141.292, and ICI 118.587 were unable to stimulate AC activity at concentrations which completely displaced 125I-CYP binding. In comparison, norepinephrine stimulated AC activity to the same level as isoproterenol (three to four times basal activity) and the beta 2-selective agonist terbutaline caused some 50% of maximal AC stimulation. This raises the question whether ISA is due to AC activation. The effect upon AC activation and 125I-CYP binding of drugs with beta-selectivity shows that both beta 1- and beta 2-receptors are coupled to the AC.
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PMID:Relative potencies of various beta-adrenoceptor antagonists (BAA) at the level of the human myocardial beta-adrenoceptor-adenylate cyclase (AC) complex. Is intrinsic sympathomimetic activity (ISA) due to AC activation? 287 14

The density of beta adrenoceptors, the relative number of beta 1 and beta 2 adrenoceptor subtypes, and adenylate cyclase activity were studied in preparations from atrial biopsy specimens of 32 patients with coronary heart disease. Six patients were not receiving beta blocking agents, whereas the others were treated with different beta blocking drugs (timolol, propranolol, pindolol, metoprolol, and atenolol). Clinical and haemodynamic variables were similar in the different groups of patients. Beta adrenoceptor density was 17% significantly lower in the non-treated group than in the groups treated with beta blocking drugs. Among these, the group treated with pindolol, a drug with intrinsic sympathomimetic activity, had receptor densities that were 38% significantly higher than those treated with other beta blocking drugs and 51% significantly higher than the non-treated group. The relative numbers of beta 1 and beta 2 adrenoceptor subtypes were very similar in the different groups (beta 1 receptors 75-80%, beta 2 receptors 20-25%). A significant increase in the ratios of terbutaline stimulated to basal and terbutaline stimulated to isoproterenol stimulated adenylate cyclase activities was found in patients treated with beta 1 selective blockers (metoprolol, atenolol), indicating that beta 1 selective drugs may improve beta 2 receptor-adenylate cyclase coupling. In contrast, pindolol caused a significant reduction in the ratio of terbutaline stimulated to isoproterenol stimulated adenylate cyclase activity, indicating that this drug may cause a reduction in beta 2 receptor-adenylate cyclase coupling efficacy. Thus treatment with beta blocking agents causes upregulation of human myocardial beta receptor density. Intrinsic sympathomimetic activity seems to favour receptor upregulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of beta blocking agents on the density of beta adrenoceptors and adenylate cyclase response in human myocardium: intrinsic sympathomimetic activity favours receptor upregulation. 287 24

beta-Adrenergic receptor (beta AR) blocking agents with intrinsic sympathomimetic activity (ISA) can induce modest increases in beta AR-stimulated activity, such as rate and force of contraction in cardiac tissue. The molecular basis for this activity has been elusive. Previous studies have suggested that these compounds do not stimulate cyclic AMP (cAMP) formation even though activation of adenylate cyclase is the generally accepted mechanism for beta AR promotion of target cell response. In the current studies, we show that several beta AR antagonists with ISA (dichloroisoproterenol, pindolol, and celiprolol) stimulate cAMP accumulation five-, two-, and threefold, respectively, in S49 lymphoma cells, but only if cells are simultaneously incubated with the diterpene forskolin. The KI values observed for inhibition of isoproterenol-stimulated cAMP accumulation or of beta AR [( 125I]iodocyanopindolol) binding for each of the beta blockers with ISA were comparable in magnitude to their respective EC50 values for forskolin-potentiated cAMP accumulation. The forskolin-potentiated responses of these compounds were abolished by the beta AR-antagonist propranolol. These results indicate that the ISA of beta-blocking drugs most likely results from a modest beta AR-mediated stimulation of adenylate cyclase activity. The results further suggest that treatment of target cells with forskolin provides a means to define partial agonism at receptors that are linked to stimulation of adenylate cyclase.
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PMID:Molecular mechanism of beta-adrenergic receptor blockers with intrinsic sympathomimetic activity. 290 94

The effects of isoprenaline, terbutaline and forskolin were examined on cyclic nucleotide concentrations and contractile responses in guinea-pig isolated soleus muscles. Isoprenaline and terbutaline induced rapid, concentration-related reductions in the tension and degree of fusion of subtetanic contractions of the soleus muscle. These changes were associated with increases (about 2 fold) in the levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in the muscle cells. Propranolol competitively inhibited these responses. Forskolin failed to elicit a sympathomimetic response in the soleus muscles despite increasing (by about 20 fold) the intracellular concentration of cyclic AMP. Forskolin also failed to potentiate the effects induced by isoprenaline. The levels of cyclic GMP in the soleus were increased by isoprenaline (about 1.5 fold) and forskolin (about 2.5 fold). Terbutaline was without effect on cyclic GMP levels. These data suggest either that cyclic AMP is not involved as the mediator underlying beta-adrenoceptor-induced changes in contractility of slow contracting skeletal muscles or that forskolin does not stimulate the particular adenylate cyclase that leads to appropriate increases in cyclic AMP in those functional compartments associated with modulation of intracellular Ca2+ movements. Cyclic GMP is not involved in modifying changes in contractility of the soleus muscle.
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PMID:Cyclic nucleotides and contractility of isolated soleus muscle. 298 3

Mechanisms of denervation supersensitivity to sympathomimetic amines were studied in conscious animals. Norepinephrine, 0.1 micrograms/kg, increased left ventricular dP/dt significantly more (4208 +/- 828 mm Hg/sec) in dogs with cardiac denervation than in intact dogs (1029 +/- 280 mm Hg/sec), P less than 0.01, whereas responses to isoproterenol were similar in both groups. Denervation supersensitivity to isoproterenol could be demonstrated only after opposing reflex effects were blocked. After ganglionic blockade, norepinephrine still induced 2- to 3-fold greater increases in left ventricular dP/dt and 3- to 7-fold greater increases in heart rate in cardiac-denervated dogs, whereas isoproterenol and prenalterol, not taken up by presynaptic nerve endings, elicited only 40%-50% greater increases in left ventricular dP/dt and heart rate in dogs with cardiac denervation. The density of beta-adrenergic receptors [( 3H]dihydroalprenolol) was elevated (P less than 0.01) in denervated left ventricles (105 +/- 6.9 fmol/mg protein, n = 8) compared to normal left ventricles (70 +/- 6.3 fmol/mg protein, n = 12). This was accompanied by enhanced isoproterenol-mediated adenylate cyclase activity. However, muscarinic cholinergic receptor density, [( 3H]quinuclidinyl benzilate), decreased from control levels of 251 +/- 11 fmol/mg protein (n = 7) to 193 +/- 14 fmol/mg protein (n = 6). Thus, chronic cardiac denervation results in upregulation of the beta-adrenergic receptor and down-regulation of the muscarinic receptor. The increased beta-adrenergic receptor density and adenylate cyclase stimulation correlated well with the amount of denervation supersensitivity to isoproterenol and prenalterol, but accounted for only a minor fraction of denervation supersensitivity to norepinephrine. The major mechanism of denervation supersensitivity to norepinephrine appears to involve lack of the norepinephrine reuptake.
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PMID:Mechanisms of supersensitivity to sympathomimetic amines in the chronically denervated heart of the conscious dog. 298 20


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