PHARMACOLOGICAL 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

Objectives. The goal of the present study was to evaluate the antifibr illatory and hemodynamic effects of pharmacologic muscarinic activatio n and to compare them with those of betaadrenergic blockade. Backgroun d. Recent studies suggest a correlation between increased vagal activi ty and a reduced incidence of sudden cardiac death. Electrical stimula tion of the vagus nerve reduces the incidence of ventricular fibrillat ion in a conscious animal model of sudden cardiac death. Methods. Elev en dogs with healed anterior myocardial infarction, in which a 2-min l eft circumflex coronary artery occlusion during exercise caused ventri cular fibrillation, were studied. They underwent subsequent tests with saline solution, propranolol (1 mg/kg body weight), methacholine (0.5 mug/kg per min) and oxotremorine (8 mug/kg). Results. In the test wit h saline solution, 100% of the dogs developed ventricular fibrillation ; this occurred in only 10% of the tests with propranolol (95% confide nce interval 0.2% to 44%; p < 0.001), 60% of the tests with methacholi ne (95% confidence interval 26% to 88%, p = 0.05) and 37.5% of the tes ts with oxotremorine (95% confidence interval 8% to 75%, p = 0.005). P ropranolol and oxotremorine significantly reduced heart rate compared with saline solution, whereas methacholine did not. Propranolol signif icantly reduced maximal first derivative of left ventricular pressure, (dP/dt(max)), particularly during myocardial ischemia, compared with the other treatments (2,391 +/- 582 mm Hg/s [mean +/- 1 SD] with propr anolol 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. Propranoiol was extremely effective against vent ricular fibrillation. Methacholine and oxotremorine provided a signifi cant, although less marked, protection and caused much less impairment of contractility compared with propranolol. Muscarinic receptor activ ation may represent a new approach to prevention of sudden cardiac dea th, particularly when beta-blockers are contraindicated and negative i notropic effects are to be avoided.