Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The cardiac actions of amiodarone, a benzofuran derivative used in the treatment of angina pectoris, have been compared with those of (+/-)-propranolol in anaesthetized dogs.2. After three successive intravenous injections of propranolol, 0.5 mg/kg, had reduced the heart rate by 25%, a fourth dose had no further negative chronotropic action, but amiodarone, 10 mg/kg intravenously, at this point reduced the heart rate by 23%.3. Amiodarone, 10 mg/kg intravenously, reduced, but did not abolish, cardiac responses to isoprenaline, 2 mug/kg intravenously. Subsequent successive injections of 10 mg/kg of amiodarone did not further block the responses to isoprenaline, but propranolol, 1 mg/kg intravenously, abolished them.4. Amiodarone reduced cardiac chronotropic and inotropic responses to glucagon, which were not affected by propranolol.5. Cardiac output was increased 5 min after amiodarone, 10 mg/kg intravenously, but at 10 min and thereafter it did not differ from control values. Propranolol, 1 mg/kg intravenously, reduced cardiac output by 17% at 5 min, and by 30% after 30 min.6. From this and other evidence which is discussed, it is concluded that the cardiac actions of amiodarone are not produced by competitive blockade of beta-adrenoceptors.
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PMID:Cardiac actions in the dog of a new antagonist of adrenergic excitation which does not produce competitive blockade of adrenoceptors. 548 43

Class III (Vaughan-Williams classification) antiarrhythmic drugs prolong the cardiac action potential without affecting depolarisation. The 3 class III drugs currently in general use are amiodarone, sotalol and bretylium. The presenting features of acute toxicity are different for each agent and are, therefore, discussed separately. Several new class III antiarrhythmic agents are under development, including dofetilide and d-sotalol, but specific data on overdoses of these potent class III drugs are not yet available. Amiodarone toxicity following acute overdose is rare because poor bioavailability and a large volume of distribution limit the peak serum concentration. Toxicity is low even if high serum concentrations are reached. The major risks from acute overdose are hypotension (intravenous administration only) and arrhythmia if other factors, such as hypokalaemia or additional antiarrhythmic agents are present. Management is chiefly directed at reducing absorption with activated charcoal or cholestyramine, and monitoring for arrhythmia. Sotalol is a beta-blocker with additional class III activity. Oral bioavailability is high, and overdosed patients can present with bradycardia, hypotension and major haemodynamic collapse. The combination of bradycardia and prolongation of the QT interval is associated with malignant arrhythmias such as torsade de pointes. Management principles include observation and correction of bradycardia with endocardial pacing, intravenous adrenergic drugs and glucagon. The risk of arrhythmia can be substantially reduced by intravenous potassium and magnesium supplements. d-Sotalol is a potent class III drug devoid of beta-blocking activity and may be expected to share the proarrhythmic affects of the racemic mixture in overdose, without pronounced hypotension and bradycardia. Intravenous bretylium in overdose causes an initial hypertensive effect, followed by profound hypotension from systemic vasodilation. Management is directed at controlling hypotension with volume expansion and norepinephrine (noradrenaline).
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PMID:Class III antiarrhythmics in overdose. Presenting features and management principles. 812 65

1. The effects of SR 33589 and amiodarone on the cardiac beta-adrenoceptor were studied in vitro and after chronic treatment by means of [125I]-(-)-iodocyanopindolol ([125I]-(-)-CYP) binding and measurement of adenylate cyclase activity. 2. Binding of [125I]-(-)-CYP was inhibited in a dose-dependent manner by SR 33589 (IC50=1.8 +/- 0.4 microM, nH=0.93 +/- 0.06) and amiodarone (IC50=8.7 +/- 2.0 microM, nH=9.2 +/- 0.03). Saturation binding experiments indicated a non-competitive interaction such that SR 33589 (1 and 3 microM) and amiodarone (5 and 10 microM) reduced the Bmax of [125I]-(-)-CYP binding without any effect on the KD. Kinetic studies showed that the rate of association of [125I]-(-)-CYP was unchanged while the rate of dissociation was increased both in the presence of SR 33589 (10 microM) and amiodarone (30 microM).3. Under the same conditions, the receptor stimulated adenylate cyclase activity was inhibited in a dose-dependent, but non-competitive manner, by SR 33589 (isoprenaline-, glucagon- and secretin-stimulated enzyme inhibited 50% at 6.8 +/- 0.6 microM, 31 +/- 10 microM and 12 +/- 3 microM, respectively) while the basal, GTP- and GPP(NH)p-stimulated enzyme was inhibited by 5-10% and the NaF and forskolin-stimulated enzyme by 50% at 500 microM. Amiodarone exhibited a similar pattern of inhibition. 4. After chronic oral treatment (50, 100, 150 mg kg(-1) per day, 14 days), both SR 33589 and amiodarone produced a dose-dependent decrease in Bmax without any effect on KD as determined from [125I]-(-)-CYP saturation experiments and a decrease of the isoprenaline- and glucagon-stimulated adenylate cyclase activity without any effect on basal enzyme activity or activity when stimulated by agents acting directly on regulatory catalytic units. 5. Unlike amiodarone, SR 33589 does not contain iodine substituents. Plasma levels of T3, T4, and rT3 were changed after SR 33589 treatment except a decrease in T4 level at the highest dose whilst the T4 T3 ratio and the level of rT3 were dose-dependently increased by amiodarone treatment. 6. In vitro, SR 33589 and amiodarone were characterized as non-competitive beta-adrenoceptor antagonists. Chronic treatment led to a down-regulation of the beta-adrenoceptor; the down-regulation cannot be attributed to an indirect effect mediated by the thyroid hormones. To reconcile these opposing observations, we propose that SR 33589 and amiodarone interact with the beta-adrenoceptor at a site close to the intracellular loops which are involved in the coupling with Gs and contain the phosphorylable sites.
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PMID:Interaction of the antiarrhythmic agents SR 33589 and amiodarone with the beta-adrenoceptor and adenylate cyclase in rat heart. 864 Mar 31

The active neurotoxin of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridinium (MPP+), exerts its lethal effect by inhibiting Complex I of the electron transport chain (ETC). MPP+ shuts down aerobic oxidative phosphorylation and ETC-mediated ATP synthesis. The present investigation examines anaerobic survival during MPP+ toxicity in murine neuroblastoma cells Neuro 2-A (N2-A). MPP+ addition to the cells resulted in a reduction in cell viability, mitochondrial O(2) consumption (MOC) and ATP concentration in a dose-dependent manner. However, the addition of 10 mM of D-(+)-glucose prevented MPP+ toxicity, attenuated the loss of ATP, but did not reverse the complete inhibition of MOC, indicating substrate level phosphorylation and explicit anaerobic survival. Glucose addition prevented MPP+-mediated drop in DeltaPsim, endoplasmic reticulum and intracellular organelle membrane potential tantamount to an increase of cell viability. Secondly, we examined the metabolic regulation of pyruvate dehydrogenase (PDH) and carnitine palmitoyl transferase (CPT) activities during glucose rescue. These enzymes exert control over acetyl CoA reservoirs in the mitochondria during aerobic metabolism. DL-6,8-Thioctic acid (PDH prosthetic group) and insulin slightly augmented metabolic rate, resulting in enhanced vulnerability to MPP+ in a glucose-limited environment. Additional glucose prevented these effects. Amiodarone (CPT inhibitor) and glucagon did not hamper or potentiate glucose rescue against MPP+. These data support strict anaerobic glucose utilization in the presence of toxic levels of MPP+. Moreover, the findings indicate that MPP+ exerts two distinct modes of toxicity (fast and slow death). With MPP+ (<1 mM), anaerobic glycolysis is operational, and toxicity is strictly dependent upon glucose depletion. MPP+ (1-10 mM) initiated acute metabolic collapse, with failure to sustain or switch to anaerobic glycolysis. In conclusion, overcoming energy failure against MPP+ may involve targeting rate-limiting controls over anaerobic energy pathways.
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PMID:D-(+)-glucose rescue against 1-methyl-4-phenylpyridinium toxicity through anaerobic glycolysis in neuroblastoma cells. 1254 55