Attenuation of the systemic and coronary hemodynamic effects of cocaine in conscious dogs: propranolol versus labetalol.
The interaction of cocaine with myocardial and vascular adrenoceptors is incompletely understood. The systemic and coronary hemodynamic effects of intravenous cocaine (1.5 mg/kg) were examined in dogs with and without pretreatment with propranolol (2 mg/kg i.v.) or labetalol (5 mg/kg i.v.) on different days. A total of 24 experiments was completed (three sets of experiments) using eight dogs chronically instrumented for measurement of aortic and left-ventricular pressure, left-ventricular dP/dt, subendocardial segment length, coronary blood flow, and cardiac output. Myocardial oxygen consumption was estimated from the pressure work index (PWI). Cocaine significantly (p < 0.05) increased heart rate (+51 +/- 17 bpm), mean arterial pressure (+72 +/- 10 mm Hg), left-ventricular systolic and end-diastolic pressures (+56 +/- 9 and +14 +/- 6 mm Hg, respectively), coronary blood flow (+32 +/- 10 ml/min) and the PWI (+10.0 +/- 2.3 ml O2/min/100 g). Significant reductions in stroke volume (-9 +/- 5 ml) and percent segment shortening (-7.1 +/- 1.7) were observed. These changes returned to control after 30 min. After pretreatment with propranolol, the cocaine-mediated increases in mean arterial pressure, left-ventricular systolic pressure, rate-pressure product, and the pressure work index (4.4 +/- 0.7 ml O2/min/100 g) were significantly (p < 0.05) less than those observed with cocaine alone. Cocaine also reduced contractility [dP/dt50 (-341 +/- 80 mm Hg/s)] and increased systemic vascular resistance (+2703 +/- 339 dyn.s.cm-5) in the presence of propranolol. Labetalol abolished the cocaine-mediated increases in heart rate and coronary blood flow and significantly attenuated the increases in mean arterial pressure, left-ventricular systolic pressure, cardiac output, rate-pressure product, and calculated myocardial oxygen consumption when compared to results obtained with cocaine alone. The results demonstrate that a portion of the basic dynamic effects of cocaine is mediated by stimulation of alpha and beta adrenoceptors. Combined alpha and beta adrenergic blockade reduces the hemodynamic effects of cocaine more than beta blockade alone. During antagonism of the sympathomimetic response of cocaine, direct negative inotropic actions of this drug are unmasked.
Kenny
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Department of Anesthesiology, Pharmacology, and Medicine, Medical College of Wisconsin, Milwaukee.
Pagel
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PS
Warltier
D C
DC
D000818:Animals; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects*; D007741:Labetalol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption; D011433:Propranolol / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects
D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D003042:Cocaine; D007741:Labetalol