Naloxone-induced potentiation of cardiac alpha-2 adrenoceptor-mediated depression of neurogenic tachycardia.
The objective of this investigation was to test the hypothesis that naloxone directly activates alpha-2 adrenoceptors to cause depression of neurogenic tachycardia as suggested in an earlier investigation (Naloxone-Induced Bradycardia in Pithed Rats: Evidence for an Interaction with the Peripheral Sympathetic Nervous System and Alpha-2 Adrenoceptors. J. Pharmacol. Exp. Ther. 296: 916-926, 1992). Bolus doses of naloxone in a range of 10-1000 micrograms/kg i.v., administered in the presence of sustained neurogenic tachycardia (108 +/- 10 beats per min), resulted in a dose-dependent inhibition of neurogenic tachycardia with a maximum inhibitory response of 21% and an ED50 of 55 +/- 2.3 micrograms/kg. The inhibition of the naloxone-induced inhibition of neurogenic tachycardia was antagonized by phentolamine (5 mg/kg i.v.) and rauwolscine (0.5 mg/kg i.v.), but not prazosin (0.1 mg/kg i.v.). In the absence of sympathetic nerve activity, low doses of naloxone (10-300 micrograms/kg i.v.) had no effect on heart rate. These data suggest that naloxone in lower doses (10-1000 micrograms/kg i.v.) is a partial agonist at prejunctional alpha-2 adrenoceptors. In the presence of a steady-state maximum response (21% inhibition of neurogenic tachycardia) caused by naloxone infusion (100 and 1000 micrograms/kg/min i.v.), the ED50 of the preferential alpha-2 adrenoceptor agonist, UK14304-18, was not shifted to the right, but instead shifted to the left. This suggests that naloxone-induced depression of the neurogenic tachycardia does not involve the direct activation of alpha-2 adrenoceptors, but involves the potentiation of alpha-2 adrenoceptor-mediated inhibition of heart rate through an unknown mechanism.
Slavik
K J
KJ
Department of Pharmacology, University of Houston, Texas.
Szilagyi
J E
JE
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects* / Q000294:innervation; D008297:Male; D009206:Myocardium / Q000648:ultrastructure*; D009270:Naloxone / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000502:physiology; D013610:Tachycardia / Q000188:drug therapy* / Q000503:physiopathology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D009270:Naloxone; D000068438:Brimonidine Tartrate