ATTENUATION OF THE CARDIAC EFFECTS OF COCAINE BY DIZOCILPINE

Cocaine abuse causes autonomic and cardiovascular effects that may be life threatening. Attenuation of cocaine-induced seizures has been pro duced by the noncompetitive antagonist of the N-methyl-D-aspartate rec eptor channel complex, dizocilpine. The purpose of the present study w as, first, to determine effects of dizocilpine on the incidence of pac ing-induced ventricular arrhythmias and, second, to evaluate the effec ts of dizocilpine on cocaine-induced depression of sympathetic efferen t activity to the heart. Adult dogs were anesthetized and instrumented for blood pressure and an electrocardiogram. After vagotomy and thora cotomy, electrodes and strain gauges were sutured onto the right atriu m and ventricle. A left thoracic sympathetic efferent nerve was isolat ed and stimulated for analysis of the innervation pattern. Arrhythmias were induced with programmed electrical stimulation of the heart befo re and during left cardiac sympathetic efferent nerve stimulation. The control incidence of induced arrhythmias was only 2%, which increased to 21% during left sympathetic stimulation. Cocaine (2 mg/kg iv) sign ificantly increased these to 11 and 42%, respectively. Dizocilpine (0. 5 mg/kg iv) reduced the incidence of induced ventricular arrhythmias t o 2% with cocaine (P < 0.05) and to 19% with cocaine and left sympathe tic stimulation (P < 0.01). One or two sympathetic efferent cardiac ne rves were stimulated to evaluate innervation patterns. These nerves we re severed and prepared for recording multifiber efferent neurograms. Nerve traffic was analyzed by counting positive spikes for 15 s. Contr ol activities were normalized at 100%. Within 6 min, cocaine (2 mg/kg iv) reduced the sympathetic efferent activity to 83 +/- 4% of control (n = 14 nerves). After at least 60 min of recovery, dizocilpine (0.5 m g/kg iv) was given. A second administration of cocaine reduced the sym pathetic efferent activity to only 94 +/- 3% of control. This is signi ficantly (P < 0.02) less than the initial depression. In another group of dogs pretreatment with dizocilpine before cocaine prevented the co caine-induced depression in sympathetic efferent activity to the heart (n = 16 nerves). Thus the proarrhythmic effects of cocaine and cocain e-induced sympathetic efferent depression to the heart are attenuated by the dizocilpine.