Naloxone-induced potentiation of cardiac alpha-2 adrenoceptor-mediated depression of neurogenic tachycardia

KJ Slavik and JE Szilagyi

Department of Pharmacology, University of Houston, Texas.

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.

Volume 266, Issue 1, pp. 184-191, 07/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics