Effects of halothane and other chlorinated hydrocarbons on alpha 2-adrenoceptors in the mouse cortex.
A number of general anaesthetics and organic solvents were tested for their ability to inhibit the binding of 3H-clonidine to alpha 2-adrenoceptors in mouse cerebral cortex membranes. The order of potency of the tested agents was: chloroform greater than halothane greater than trichloroethylene greater than carbon tetrachloride greater than dichloromethane. Of these agents halothane was tested further. When saturation curves of 3H-clonidine were constructed, halothane (25 mmol/l added directly to the assay) was found to induce a proportionally greater inhibition at low 3H-clonidine concentrations than at high. Computer modelling these saturation curves indicated that halothane reduced the apparent affinity of 3H-clonidine; Kd = 4.2 nmol/l in the absence of halothane and Kd = 6.0 nmol/l in its presence. Gassing the cortex membranes with 3% halothane induced a practically identical reduction in the affinity for 3H-clonidine; Kd = 4.6 nmol/l for the control versus Kd = 10.7 nmol/l for halothane. The effects of halothane was compared to that of the non-hydrolyzable GTP analog Gpp(NH)p. Gpp(NH)p in the concentration range 10(-8)-10(-3) mol/l dose-dependently reduced the binding of 1 nmol/l 3H-clonidine, the effect being essentially maximal at 10(-4) mol/l. Computer modelling of saturation curves of 3H-clonidine indicated that 0.1 mmol/l Gpp(NH)p reduced the apparent affinity of 3H-clonidine; Kd = 5.4 nmol/l in the absence of Gpp(NH)p and Kd = 9.3 nmol/l in its presence. In addition Gpp(NH)p caused some reduction in the apparent number of 3H-clonidine binding sites. The effect of halothane on 3H-clonidine binding was tested both in the absence and presence of 0.1 mmol/l 1 Gpp(NH)p. During these conditions halothane was slightly more potent in the presence of Gpp(NH)p (IC50 of halothane = 17 mmol/l) than in its absence (IC50 = 41 mmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)
Wikberg
J E
JE
Department of Pharmacology, Umeå University, Sweden.
Hede
A R
AR
Post
C
C
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003000:Clonidine / Q000378:metabolism; D006150:Guanine Nucleotides / Q000502:physiology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology*; D006843:Hydrocarbons, Chlorinated / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008345:Manganese / Q000494:pharmacology; D008566:Membranes / Q000378:metabolism; D051379:Mice; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism
D006150:Guanine Nucleotides; D006843:Hydrocarbons, Chlorinated; D011942:Receptors, Adrenergic, alpha; D006165:Guanylyl Imidodiphosphate; D008345:Manganese; D003000:Clonidine; D006221:Halothane