Naloxone potentiates contractile responses to epinephrine in isolated canine arteries.
The beneficial pressor effects of naloxone in shock have been associated with existing adrenergic systems and in particular with circulating epinephrine. Vascular interactions among alpha adrenergic receptor agents, naloxone, and selected opioids were investigated. The addition of pharmacologic concentrations of the opiate antagonist naloxone enhanced contractile responses to lower doses of epinephrine by more than 100% in isolated renal interlobar arteries. Naloxone lowered the EC50 for both epinephrine and norepinephrine but the magnitude of enhanced responses were much greater for epinephrine. Responses in the presence of naloxone to more selective alpha agonists, phenylephrine and clonidine, were also much less. The enhanced contraction cannot be demonstrated in the absence of added catecholamine and is eliminated by alpha but not by beta adrenergic blockade. Dose responses for naloxone provided an EC50 (micromolar) above those reported for known opiate receptors. Representative mu (morphiceptin), delta (DADL), and kappa (dynorphin 1-9) receptor agonists were ineffective in altering the EC50 for naloxone. Responses opposite to naloxone could be generated with pharmacological additions of another kappa opioid, dynorphin 1-8. This effect was also accomplished without shifting the EC50 for naloxone to the right, suggesting dynorphin and naloxone operate via separate mechanisms. The (+) stereoisomer of naloxone was as or more effective than (-) naloxone, adding support for a nontraditional or nonopiate receptor mechanism. Corticosterone produced responses indistinguishable from naloxone. These pharmacological steroid-like responses to naloxone are used to suggest a hypothesis based upon modulation of extra-neuronal uptake and/or adrenergic receptor desensitization mechanisms.
Caffrey
J L
JL
Department of Physiology, Texas College of Osteopathic Medicine, Fort Worth 76107.
Hathorne
L F
LF
Carter
G C
GC
Sinclair
R J
RJ
D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004399:Dynorphins / Q000494:pharmacology; D004837:Epinephrine / Q000008:administration & dosage / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011957:Receptors, Opioid / Q000502:physiology; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology
D010446:Peptide Fragments; D011957:Receptors, Opioid; D010656:Phenylephrine; D009270:Naloxone; D004399:Dynorphins; C026770:dynorphin (1-8); D003000:Clonidine; D003345:Corticosterone; D009638:Norepinephrine; D004837:Epinephrine