Prevention of ventricular fibrillation by metoprolol in a pig model of acute myocardial ischaemia: Absence of a major arrhythmogenic role for cyclic AMP

Müller, C.; Opie, Lionel H.; Hamm, Christian W.; Peisach, M.; Gihwala, D.; Steyn, J.M.; Basset, H.M.

doi:10.1016/s0022-2828(86)80901-4

Cited by 29 publications

(9 citation statements)

References 27 publications

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“…This further suggests that a plasma concentration in the 10 ng/ml range would not be associated with an antifibrillatory effect due to myocardial receptor antagonism since previously used intravenous doses of 0.2 mg/kg and 2 mg/kg racemic propranolol (4-40 times the dose as used in the present study), which would be associated with even higher plasma levels, were not effective in preventing VF in this same pig model.8 Moreover, propranolol was specifically evaluated for potential antifibrillatory efficacy in the pig, and a plasma level of 600 ng/ml was without effect in reducing the occurrence of VF after LAD coronary occlusion. 29 Baseline hemodynamic and cardiac function before occlusion is also not expected to influence or be predictive of increased myocardial vulnerability to VF in this model since no significant changes were observed in the measured indexes of cardiac inotropy and chronotropy during an 8-day laboratory adaptation protocol. This observation extends a previous finding that resting heart rates were similar in laboratory-unadapted compared with laboratoryadapted pigs despite their known difference in vulnerability to ischemia-induced VF.…”

Section: Propranolol Pharmacokineticsmentioning

confidence: 84%

Central beta-adrenergic mechanisms may modulate ischemic ventricular fibrillation in pigs.

Parker

Michael

Hartley

et al. 1990

Circulation Research

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A central noradrenergic process may permit expression of the stress-related increase in cardiac vulnerability to ventricular fibrillation (VF). Thus, the effect of central j8-adrenergic receptor blockade with L-propranolol (0.01 The high dose of L-propranolol also reduced the incidence of VF (7/15 fibrillated) compared with Ringer's solution (12/12 fibrillated) and D-propranolol (6/7 fibrillated). The lower dose of L-propranolol was without effect on VF vulnerability (7/9 fibrillated). The plasma concentration resulting from central administration of 0.05 mg/kg L-propranolol was found to be 9.05+±3.25 ng/ml, which is significantly below therapeutic antiarrhythmic blood levels. We conclude that the reduced vulnerability to ischemia-induced VF after intracerebroventricular administration of propranolol is due to alteration of a central P-adrenergic receptor-mediated phenomenon as opposed to an effect on the heart directly or to nonspecific membrane stabilization. (Circulation Research 1990;66:259-270) V arious psychological risk factors have been related epidemiologically to cardiac rhythm disturbances in the presence and absence of coronary artery disease.1-6 These rhythm disturbances include ventricular tachycardia and ventricular fibrillation (VF), the underlying mechanisms of sudden cardiac death. Although some of the psychological stressors are clearly related to acute phasic stress and imminent emotional distress accompanied by hemodynamic alterations consistent with autonomic imbalance, many are related to more tonic From the section of Cardiovascular Sciences (G.W.P., L.H.M.,

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Section: Propranolol Pharmacokineticsmentioning

confidence: 84%

Central beta-adrenergic mechanisms may modulate ischemic ventricular fibrillation in pigs.

Parker

Michael

Hartley

et al. 1990

Circulation Research

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“…An accumulation of mitochondrial calcium is potentially harmful (Lehninger et al, 1978). Tissue lactate levels can rise to 30-50 ~LM/g fresh weight after coronary ligation in the pig (Muller et al, 1986). Thus adverse effects of high levels of neutral lactate could well contribute to the overall mechanism of ischemic damage.…”

Section: Is It Correct To Call Nadh2 and Protons The End Products Of mentioning

confidence: 99%

Myocardial ischemia?Metabolic pathways and implications of increased glycolysis

Opie

1990

Cardiovasc Drug Ther

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Evidence is reviewed that favors the hypothesis that maintenance of glycolysis plays a special role in protecting membrane function in ischemia. Therefore all procedures stimulating glycolytic flux should be beneficial in ischemia, and procedures inhibiting flux should be harmful. However, a crucial consideration is the coronary flow rate. In severe ischemia, accumulation of protons, derived not directly from glycolytic flux but from the breakdown of ATP and from proton-producing cycles, will tend to inhibit glycolysis and to minimize any benefit from increased glycolytic flux. Therefore maintenance of intracellular pH is crucial to the concept of the benefits of glycolysis. It also follows that the severity of ischemia can determine whether or not enhanced glycolysis has a beneficial effect. It is argued that a multiple approach, including enhanced glycolytic flux, control of intracellular pH, and improved coronary flow, constitutes the combination most likely to benefit ischemia.

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“…In this model, a distinct early phase (1B) of ventricular arrhythmias [14] is evident between 15 and 35 minutes after ligation [1,9]. All episodes of VF, almost all episodes of VT, and clusters of VPS are confined to this period.…”

Section: Ventricular Arrhythmiasmentioning

confidence: 89%

“…Arrhythmias were categorized as ventricular premature systoles (VPS), ventricular tachycardia (VT), and ventricular fibrillation (VF) as before [9]. If defibrillation could not be accomplished within 90 seconds, the experiment was terminated.…”

Section: Methodsmentioning

confidence: 99%

Bucindolol, a beta blocker, decreased ventricular fibrillation and maintained mechanical function in a pig model of acute myocardial ischemia

Müller

Opie

Pineda³

et al. 1992

Cardiovasc Drug Ther

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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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Prevention of ventricular fibrillation by metoprolol in a pig model of acute myocardial ischaemia: Absence of a major arrhythmogenic role for cyclic AMP

Cited by 29 publications

References 27 publications

Central beta-adrenergic mechanisms may modulate ischemic ventricular fibrillation in pigs.

Central beta-adrenergic mechanisms may modulate ischemic ventricular fibrillation in pigs.

Myocardial ischemia?Metabolic pathways and implications of increased glycolysis

Bucindolol, a beta blocker, decreased ventricular fibrillation and maintained mechanical function in a pig model of acute myocardial ischemia

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