Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1323099 (sympathomimetic)
 2,957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bretylium tosylate (Bretylol) has recently been approved for parenteral use against resistant ventricular arrhythmias. The pharmacologic action of bretylium is complex, and its antiarrhythmic action differs significantly from other drugs. Bretylium is an adrenergic neuronal blocking agent taken up selectively at peripheral adrenergic nerve terminals, where it initially releases norepinephrine (sympathomimetic effect) and then produces adrenergic neuronal blockade. It has direct cardiac membrane effect to prolong action potential duration and effective refractory period but, unlike other membrane active antiarrhythmic agents, does not depress conduction velocity or automaticity. Bretylium increases ventricular fibrillation threshold and prevents the decrease in ventricular fibrillation threshold associated with myocardial ischemia. It does not depress myocardial contractility. Clinical studies have shown parenteral bretylium to be effective in suppressing ventricular arrhythmias, particularly recurrent, drug resistant ventricular tachycardia or ventricular fibrillation.
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PMID:Bretylium tosylate: a newly available antiarrhythmic drug for ventricular arrhythmias. 38 Apr 36

The antiarrhythmic, adrenergic-stimulating and blocking properties of bretylium and a structural analog UM-360, o-iodobenzyl trimethylammonium chloride, were studied in the anesthetized dog. Bretylium produced an initial sympathomimetic effect with a subsequent blockade of cardiac responses to sympathetic nerve stimulation. Bretylium was observed to produce an antifibrillatory effect when the vulnerability to fibrillation was measured as the current required to evoke ventricular fibrillation (ventricular fibrillation threshold) or the spontaneous development of ventricular fibrillation in response to a one-stage occlusion of the left anterior descending coronary artery for 20 minutes followed by release. In animals intoxicated with ouabain, however, bretylium was not effective in reversing the ventricular tachycardia. UM-360, in contrast to bretylium, did not produce adrenergic stimulation or blockade of sympathetic neuronal activity. UM-360, however, produced a marked antifibrillatory effect by increasing the electrical threshold to ventricular fibrillation and reducing the incidence of ventricular fibrillation in response to coronary artery occlusion. The results of this study suggest that the quaternary ammonium structure, as possessed by bretylium and UM-360, may be of significance with respect to the antiarrhythmic and antifibrillatory effects of these agents.
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PMID:The antiarrhythmic and antifibrillatory actions of bretylium and its o-iodobenzyl trimethylammonium analog, UM-360. 112 18

1 The ventricular fibrillation threshold (VFT) was measured in the isolated heart of the rabbit perfused via the aorta with McEwen's solution at 37 degrees C by applying a single 10 ms pulse of current during the vulnerable period of late systole. The arrhythmia induced was either fibrillation or a rapid tachycardia. 2 The catecholamines adrenaline, noradrenaline and isoprenaline, but not dopamine, when infused at rates which produced similar moderate effects on cardiac rate and force, significantly lowered the VFT; it was reduced slightly more by adrenaline than by the other two. Phenylephrine and methoxamine were ineffective. Only those sympathomimetic amines which lowered the VFT also shortened the vulnerable time, i.e. minimal time after the R-wave of the ECG at which the pulse had to be applied to induce the arrhythmia. 3 The lowering effect of adrenaline on the VFT was not influenced by phentolamine but was blocked by propranolol and pindolol. 4 Chloroform potentiated the lowering effect of adrenaline, but not that of isoprenaline, on the VFT. Carbachol did not alter the effect of adrenaline on the VFT. 5 The results indicate that adrenaline, noradrenaline and isoprenaline lower the VFT by a direct action on the cardiac musculature and that this effect is mediated via beta-adrenoceptors.
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PMID:The effect of sympathomimetic amines on the ventricular fibrillation threshold in the rabbit isolated heart. 112 90

Bucindolol is a new beta blocker with marked vasodilatory properties and intrinsic sympathomimetic activity. We tested its potential effect against ventricular fibrillation (VF), in a pig model of acute myocardial ischemia. Bucindolol 6 mg/kg IV was administered in two equally divided doses, the first 30 minutes prior to, and the second 10 minutes after, ligation of the anterior descending coronary artery (CAL) in anesthetized open-chest pigs. Bucindolol decreased the incidence of VF to 1/11 versus 14/16 in the control group (p less than 0.005). Bucindolol also decreased the duration of ventricular tachycardia, 15 +/- 8 seconds versus 104 +/- 32 seconds in the control group (p less than 0.01). Bucindolol maintained LVmaxdP/dt at predrug and pre-CAL values, whereas LVmaxdP/dt was decreased by CAL in the control group. Bucindolol decreased arterial pressure and heart rate. Bucindolol increased blood flow in the peripheral ischemic zone (24.6 +/- 1.8% versus 16.2 +/- 1.7% (percent of pre-CAL value) in controls, p less than 0.002), as well as in the nonischemic zones (periischemic zone: 126.4 +/- 6.1% versus 96.7 +/- 4.8% in the control group, p less than 0.0005; remote nonischemic zone: 126.6 +/- 7.1% versus 87.1 +/- 4.3% of pre-CAL value in the control group, p less than 0.0001). Bucindolol had marked antiarrhythmic effects that were associated with beneficial effects on the mechanical function of the left ventricle and on blood flow to the ischemic myocardium.
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PMID:Bucindolol, a beta blocker, decreased ventricular fibrillation and maintained mechanical function in a pig model of acute myocardial ischemia. 135 66

Patients who have sustained greater than or equal to 1 myocardial infarcts are at high risk for sudden death or reinfarction; the risk is highest for those with lowest ventricular ejection fraction, continuing myocardial ischemia and asymptomatic high-density and complex premature ventricular contractions. At present, beta blockers when given prophylactically are the only agents that reduce the incidence of sudden death and reinfarction in survivors of myocardial infarction (MI) in the first 2 years. The beneficial effect was shown to correlate with a reduction in heart rate, the effect being absent or deleterious with beta blockers with marked sympathomimetic activity. The effects of beta blockers on ventricular fibrillation appeared to be dissociated from those on premature ventricular contractions. Trials with calcium antagonists indicate that these drugs had no effect or increased the mortality rate. The divergent effect of beta blockers and calcium antagonists is unexplained but may be due in part to a lack of bradycardiac effect of calcium antagonists; there were no differences in effect among different calcium antagonists. Data from trials involving class I antiarrhythmic agents indicate that agents acting by depression of cardiac conduction are either devoid of effect or produce a modest increase in mortality. Results of the Cardiac Arrhythmia Suppression Trial, employing the newer class I agents flecainide and encainide, were used to determine whether the suppression of premature ventricular contractions in the survivors of acute MI reduces mortality. Flecainide and encainide suppressed premature ventricular contractions greater than 80%, but resulted in an increased mortality rate undoubtedly due to a marked proarrhythmic effect. Whether these data can be extrapolated to all class I agents is uncertain. Preliminary data with class III antiarrhythmic agents suggest that these agents, especially amiodarone, similarly to beta blockers, have the potential to reduce mortality in survivors of MI. Evolving data suggest that in the secondary prevention of morbid events in the survivors of acute MI, the focus must shift away from antiarrhythmic agents that delay conduction and toward beta blockers and antifibrillatory actions resulting from a prolongation of refractoriness.
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PMID:Advantages of beta blockers versus antiarrhythmic agents and calcium antagonists in secondary prevention after myocardial infarction. 169

Unexpected, sustained ventricular tachyarrhythmia after cardiac operations is differentiated from sustained ventricular tachycardia and ventricular fibrillation from known antecedent causes, such as recent or perioperative myocardial infarction, low cardiac output, preoperative ventricular arrhythmia, sympathomimetic drugs, drug toxicity, and metabolic abnormalities. Sixteen of 2364 patients (0.68%) who underwent heart operations met strict exclusion criteria for unexpected sustained ventricular tachyarrhythmia that occurred 1 hour to 12 days after operation. Recurrent ventricular tachyarrhythmias occurred in 12 patients; three died (21%), despite resuscitation from the initial episode. All patients had significant preoperative left ventricular dysfunction and 14 had ejection fractions below 30%. Fifteen of the 16 patients had monomorphic ventricular tachycardia at the initial episode. Empirically prescribed therapy was not effective in suppressing ventricular tachyarrhythmias inducible by programmed stimulation during postevent electrophysiologic studies in 10 of the 13 survivors. Inducibility was eventually prevented by drugs in nine patients, three patients received automatic implantable cardiac defibrillators, and one patient underwent successful catheter ablation of ventricular tachycardia. No patient died of recurrent ventricular tachyarrhythmias during the follow-up of 8 to 55 (mean 29) months after hospital discharge.
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PMID:Unexpected, sustained ventricular tachyarrhythmia after cardiac operations. 196 Sep 92

Results obtained in the past 3 years in patients referred with acute myocardial infarction (AMI) and cardiogenic shock for a mechanical bridge to urgent transplantation permit one to assess the real impact of the present strategy in clinical practice. Ten patients (mean age = 49) were admitted in serious condition (CI = 1.8 +/- 0.2 L/min/m2, PCWP = 28 +/- 6 mmHg, systolic aortic pressure = 88 +/- 20 mmHg, urine output 11 +/- 20 ml/hr) and were treated by maximal sympathomimetic support and i.v. enoximone. Two had to be implanted with a total artificial heart (TAH) and one with a left ventricular assist device (LVAD) for recurrent fibrillation despite hemodynamic improvement, within 8 hr. Two have received transplants and are living well after 20 months. Seven who initially improved markedly have been listed as urgent transplant candidates: two of these have been successfully transplanted, and three died suddenly after 6, 25, and 45 days, respectively. One has undergone successful coronary surgery. One patient (age 62, diabetic) was secondarily rejected for a transplant and died. This experience clearly shows that despite initial spectacular hemodynamic improvement, which was due to optimized medical management, death rate before transplant because of sudden ventricular fibrillation remains unacceptably high. This should prompt early mechanical support, with less invasive systems, in patients with AMI.
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PMID:The real impact of mechanical bridge strategy in patients with severe acute infarction. 214 54

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

The electrophysiological effects of bethanidine and meobentine were studied on isolated canine cardiac tissues and the in situ dog heart using standard techniques. The "direct" electrophysiological effects of bethanidine (in the beta-adrenergic-blocked Purkinje fiber) resemble the effects of meobentine in the normal canine Purkinje fiber; both drugs produce use-dependent decreases of the maximum rate of depolarization of phase 0 and action potential amplitude. In addition, meobentine prolongs action potential duration (100%) of Purkinje fibers. In ventricular muscle cells, the only significant effect of meobentine is a decrease in the maximum rate of depolarization. In studies of ouabain-induced tachycardias and 24-h infarct-induced ventricular arrhythmias, bethanidine tends to increase heart rate and/or exacerbate the ectopic activity (due to its sympathomimetic effects), whereas meobentine tends to reduce heart rate and restore normal sinus rhythm. Both bethanidine and meobentine increase ventricular fibrillation threshold. This increase is evident following bethanidine injection after the subsidence of the sympathomimetic effects. Finally, moderate increases of ventricular fibrillation threshold following treatment with meobentine are accompanied by partial cardiac sympathetic blockade, as indicated by reduced chronotropic responses to stellate ganglion stimulation. The antiarrhythmic and antifibrillatory effects of bethanidine and meobentine may be explained by the use-dependent effects of these drugs on phase 0 of the action potential and by their sympatholytic actions on the autonomic nervous system. Meobentine may, in addition, exert antiarrhythmic effects by decreasing automaticity in partially depolarized cells.
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PMID:Studies on bethanidine and meobentine: direct and indirect effects of antifibrillatory drugs. 243 45

Metoprolol and other beta-adrenergic blocking drugs are known to exert cardioprotective effects that include significant reduction in occurrence of ventricular fibrillation (VF) following myocardial ischemia and infarction. To help determine the mechanism of these cardioprotective effects, this study evaluated the effect of equipotent beta-blocking doses of metoprolol and three other beta-blockers with differing ancillary properties on ventricular fibrillation threshold (VFT) in the normal canine heart. Metoprolol tartrate (1.0 mg/kg i.v.), atenolol (0.3 mg/kg i.v.), propranolol hydrochloride (0.3 mg/kg i.v.), pindolol (0.03 mg/kg i.v.), or saline control (0.9% NaCl solution; vehicle) was given, alone and in combination with lidocaine (L), to groups of six pentobarbital (32.5 mg/kg i.v.) anesthetized mongrel dogs after control VFT and control isoproterenol-induced (ISO) positive chronotropic effects had been determined. The D- (membrane stabilizing, non-beta blocking) and L- (beta blocking) isomers of propranolol also were administered to separate groups of six anesthetized dogs in a dose of 0.3 mg/kg i.v. Blood samples (venous) were taken before drug or vehicle administration, 10 min after drug/vehicle administration and at half-hour intervals thereafter during experimentation. ISO responses and VFT were determined 5 and 15 min, respectively, after drug/vehicle administration and at half-hour intervals for a total experimental period of 165 min. VF was induced with a train of pulses (5 s, 100 Hz, 3-ms duration, 250-omega resistance) applied by bipolar platinum electrodes to a paced heart (200 beats/min). Voltage (V) was increased every 60 sec (0.25-V increments between 0-3.5 V and 0.5-V increments greater than 3.5 V) until VF occurred. Metoprolol increased VFT significantly (p less than 0.05) and maximally (max delta V = 2.3 +/- 0.7 V) at 135 min postdrug when the ISO-induced increase in heart rate was inhibited (%I ISO) by less than 53%. Max delta V was not significantly increased following i.v. administration of atenolol (0.8 +/- 0.6 V), pindolol (0.1 +/- 0.1 V), or saline (0.1 +/- 0.1 V). Max delta V was 0.5 +/- 0.2 in the D-propranolol-treated group and 0.5 +/- 0.3 in the L-propranolol-treated group. These values did not differ from max delta V obtained in the propranolol-treated group (0.6 +/- 0.4 V). Changes in VFT for all groups were, over time, negatively correlated with %I ISO and were not dependent on membrane stabilizing effect (metoprolol, propranolol (D,DL), pindolol), intrinsic sympathomimetic activity (pindolol), or cardioselectivity (metoprolol, atenolol).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of metoprolol, alone and in combination with lidocaine, on ventricular fibrillation threshold: comparison with atenolol, propranolol, and pindolol. 243 44


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