Role of L-type calcium channels on yohimbine-precipitated clonidine withdrawal in vivo and in vitro.
This study was designed to elucidate the possible participation of L-type calcium channels in the expression of clonidine-withdrawal precipitated by yohimbine in clonidine-dependent animals. Mice implanted for 5 days with osmotic minipumps containing the alpha 2-adrenoceptor agonist clonidine showed symptoms of a withdrawal syndrome (jerks, headshakes, defecations and weight loss) when yohimbine, an alpha 2-adrenoceptor antagonist, was injected. Similarly, isolated rat ilea incubated with clonidine in vitro showed a withdrawal contracture when yohimbine was added to the organ bath. The effects of L-type calcium channel blockers (verapamil and diltiazem) and the stimulant Bay K 8644 on these two different types of withdrawal responses were evaluated. A dose-dependent decrease in yohimbine-precipitated clonidine withdrawal in vivo was observed when verapamil (10-40 mg/kg, s.c. and 120 micrograms/mouse, i.c.v.) or diltiazem (5-20 mg/kg, s.c. and 160 micrograms/mouse, i.c.v.) were administered to mice dependent on clonidine. No effect was found after Bay K 8644 (0.5-5 mg/kg, s.c. and 1-5 micrograms/mouse) was injected under these conditions. In vitro, both verapamil (0.1-5 microM) and D-cis-diltiazem (1-50 microM) concentration-dependently reduced the height of the yohimbine-precipitated withdrawal contracture in rat ileum incubated with clonidine. Furthermore, the effect of diltiazem was stereospecific, as D-cis-diltiazem 10 microM markedly inhibited clonidine withdrawal, whereas the same concentration of L-cis-diltiazem had no effect. In contrast, the calcium channel stimulant Bay K 8644 (0.1-1 microM) increased the height of the ileum withdrawal contracture.(ABSTRACT TRUNCATED AT 250 WORDS)
Barrios
M
M
Department of Pharmacology, Medical School, University of Granada, Spain.
Robles
I
I
Baeyens
J M
JM
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D003000:Clonidine / Q000008:administration & dosage; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D005260:Female; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007536:Isomerism; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D014700:Verapamil / Q000494:pharmacology; D015016:Yohimbine / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D015220:Calcium Channels; D004343:Drug Implants; D015016:Yohimbine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D004110:Diltiazem; D003000:Clonidine