Nifedipine, an L-type calcium channel blocker, restores the hypnotic response in rats made tolerant to the alpha-2 adrenergic agonist dexmedetomidine.
Rats were made tolerant to the hypnotic effects of the alpha-2 adrenergic agonist dexmedetomidine by a 7- or 14-day continuous systemic administration of the same, and the ability of nifedipine to reverse dexmedetomidine tolerance was assessed. Acute administration of nifedipine (10 mg/kg i.p.) restored the hypnotic response to dexmedetomidine in the alpha-2 tolerant rats. Concurrent administration of nifedipine during induction of tolerance, either partially (continuous administration 10 mg/kg/day delivered by minipumps) or completely (twice daily injections, 20 mg/kg s.c.) restored hypnotic responsiveness to control levels. Induction of tolerance reduced the affinity of [3H]PN200-110 for the L-type calcium channel. Chronically administered nifedipine treatment (20 mg/kg s.c. twice daily), at doses that partially restored the behavioral response to normal, did not change ligand binding affinity of [3H]PN200-110. An increase in Bmax for [3H]PN200-110 was noted in the dexmedetomidine tolerant state which did not change with chronic nifedipine. In naive rats, the phosphodiesterase inhibitor rolipram (275 microg/kg i.p.), mimicked the state of tolerance, as it resulted in a decreased hypnotic response to dexmedetomidine. Nifedipine (10 mg/kg i.p.) also reversed the rolipram-induced attenuation of the hypnotic response to dexmedetomidine. These data implicate a role for the L-type calcium channel in the mechanism of the hypnotic response in alpha-2 tolerant rats and suggest the involvement of the cAMP pathway.
Reid
K
K
Department of Anesthesia, Stanford University and Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
Guo
T Z
TZ
Davies
M F
MF
Maze
M
M
D058647:Adrenergic alpha-2 Receptor Agonists; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D020746:Calcium Channels, L-Type; D000242:Cyclic AMP / Q000502:physiology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D020926:Medetomidine; D009543:Nifedipine / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram; D013779:Tetrodotoxin / Q000494:pharmacology
D058647:Adrenergic alpha-2 Receptor Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D011760:Pyrrolidinones; D013779:Tetrodotoxin; D000242:Cyclic AMP; D009543:Nifedipine; D020889:Rolipram; D020926:Medetomidine