Pharmacologic modulation of the autonomic nervous system in the prevention of sudden cardiac death. A study with propranolol, methacholine and oxotremorine in conscious dogs with a healed myocardial infarction.

Abstract

OBJECTIVES:

The goal of the present study was to evaluate the antifibrillatory and hemodynamic effects of pharmacologic muscarinic activation and to compare them with those of beta-adrenergic blockade.

BACKGROUND:

Recent studies suggest a correlation between increased vagal activity and a reduced incidence of sudden cardiac death. Electrical stimulation of the vagus nerve reduces the incidence of ventricular fibrillation in a conscious animal model of sudden cardiac death.

METHODS:

Eleven dogs with healed anterior myocardial infarction, in which a 2-min left circumflex coronary artery occlusion during exercise caused ventricular fibrillation, were studied. They underwent subsequent tests with saline solution, propranolol (1 mg/kg body weight), methacholine (0.5 microgram/kg per min) and oxotremorine (8 micrograms/kg).

RESULTS:

In the test with saline solution, 100% of the dogs developed ventricular fibrillation; this occurred in only 10% of the tests with propranolol (95% confidence interval 0.2% to 44%; p < 0.001), 60% of the tests with methacholine (95% confidence interval 26% to 88%, p = 0.05) and 37.5% of the tests with oxotremorine (95% confidence interval 8% to 75%, p = 0.005). Propranolol and oxotremorine significantly reduced heart rate compared with saline solution, whereas methacholine did not. Propranolol significantly reduced maximal first derivative of left ventricular pressure, (dP/dtmax), particularly during myocardial ischemia, compared with the other treatments (2,391 +/- 582 mm Hg/s [mean +/- 1 SD] with propranolol vs. 4,226 +/- 1,237, 4,922 +/- 584 and 4,358 +/- 1,109 mm Hg/s with saline solution, methacholine and oxotremorine, respectively, p < 0.005).

CONCLUSIONS:

Propranolol was extremely effective against ventricular fibrillation. Methacholine and oxotremorine provided a significant, although less marked, protection and caused much less impairment of contractility compared with propranolol. Muscarinic receptor activation may represent a new approach to prevention of sudden cardiac death, particularly when beta-blockers are contraindicated and negative inotropic effects are to be avoided.

• Authors: G M De Ferrari, P Salvati, M Grossoni, G Ukmar, L Vaga, C Patrono, P J Schwartz
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 22 Issue 1 Pg. 283-90 (Jul 1993) ISSN: 0735-1097 [Print] United States
• PMID: 8509552 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Muscarinic
• Methacholine Chloride
• Oxotremorine
• Propranolol

Topics

• Animals
• Autonomic Nervous System (drug effects)
• Coronary Circulation (drug effects)
• Death, Sudden, Cardiac (etiology, prevention & control)
• Depression, Chemical
• Dogs
• Hemodynamics (drug effects)
• Male
• Methacholine Chloride (pharmacology, therapeutic use)
• Myocardial Contraction (drug effects)
• Myocardial Infarction (complications)
• Oxotremorine (pharmacology, therapeutic use)
• Propranolol (pharmacology, therapeutic use)
• Receptors, Muscarinic (drug effects)
• Ventricular Fibrillation (etiology, prevention & control)