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.
OBJECTIVE
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.
Istituto di Clinica Medica 2, Universitá di Milano, Italy.
G M
GM
De Ferrari
P
P
Salvati
M
M
Grossoni
G
G
Ukmar
L
L
Vaga
C
C
Patrono
P J
PJ
Schwartz
D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D003326:Coronary Circulation / Q000187:drug effects; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control*; D003864:Depression, Chemical; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology / Q000627:therapeutic use*; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications; D010095:Oxotremorine / Q000494:pharmacology / Q000627:therapeutic use*; D011433:Propranolol / Q000494:pharmacology / Q000627:therapeutic use*; D011976:Receptors, Muscarinic / Q000187:drug effects; D014693:Ventricular Fibrillation / Q000209:etiology / Q000517:prevention & control
D011976:Receptors, Muscarinic; D016210:Methacholine Chloride; D010095:Oxotremorine; D011433:Propranolol