Effects of adrenergic antagonists on cocaine-induced changes in respiratory function.
Cocaine-induced changes in respiratory rate (f), tidal volume (VT), total pulmonary ventilation (VE), dynamic lung compliance (Cdyn) and total pulmonary resistance (RL) were measured in anesthetized, spontaneously breathing Sprague-Dawley rats using a whole-body plethysmograph and an esophageal manometer. Carotid arterial pressure and heart rate were simultaneously monitored. An intravenous (i.v.) dose of 10 mg/kg of cocaine was lethal in all rats tested with death resulting from respiratory failure occurring between 0.25 and 1.5 min after dosing. At an i.v. dosage of 5 mg/kg, cocaine was nonlethal, although a reduction in VE was evident during the first minute after dosing. This reduction in VE was due to a decrease in f and the lack of a compensatory increase in VT. A slight decrease in RL also became evident approximately five minutes after dosing. Pretreatment with the nonselective alpha-adrenergic antagonist phentolamine (10 mg/kg) prevented the cocaine-induced depression in VE by reducing the decrease in f and blocking the inhibition of a compensatory increase in VT. In contrast, pretreatment with the nonselective beta-adrenergic antagonist propranolol (1 mg/kg) potentiated the cocaine-induced decrease in VE by enhancing the depression of f. Pretreatment with propranolol also caused a cocaine-dependent decrease in Cdyn. At a dosage of 0.3 mg/kg, labetalol, a compound possessing both nonselective alpha- and beta 1-antagonist activity (1:7) appeared to cause only a minimal potentiation of the cocaine-induced depressions in VE and f. Pretreatment with propranolol or labetalol also resulted in the death of 20% of the rats administered 5 mg/kg of cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Investigative Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
D J
DJ
Murphy
M E
ME
Walker
D A
DA
Culp
D V
DV
Francomacaro
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012119:Respiration / Q000187:drug effects*; D012129:Respiratory Function Tests; D013565:Sympatholytics / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D013565:Sympatholytics; D003042:Cocaine