Detomidine binding to guinea pig liver imidazoline receptors (I-receptors) shows marked positive cooperativity.
The binding of [3H]-idazoxan to guinea pig liver membranes was measured in the presence of 3 microM rauwolscine, which prevented the binding [3H]-idazoxan to alpha 2-adrenergic receptors. Under these conditions the radioligand bound to saturable imidazoline receptors (I-receptors) with a Kd of 18 nM and a Bmax of 665 fmol mg-1 protein. Six drugs which were used to compete for [3H]-idazoxan in the liver caused competition curves of widely varying steepness. Fitting the competition curves to the standard four parameter logistic function showed that the Hill coefficients (nH) varied from 2.02 (detomidine) to 0.43 (UK-14,304), The nH's obtained in liver for the six compounds correlated strongly (r = 0.99; P < 0.001) with the corresponding nH's obtained in a previous study on the guinea pig kidney where the drugs were also tested in competition with [3H]-idazoxan (Wikberg et al. 1992). Good correlation was also found for the Log(Ki) values of drugs determined in the two tissues (r = 0.96; P < 0.005). Whereas the standard logistic function accurately described the competition curves of the 5 drugs tested in the liver for which the competition curve Hill coefficients varied between 0.43 to 1.41 (UK-14,304, rilmenidine, histamine and d- and l-medetomidine), it did not accurately fit the detomidine competition curves. Instead the detomidine competition curves could be more accurately described by a model composed of the sum of two independent logistic functions.(ABSTRACT TRUNCATED AT 250 WORDS)
Rangel
N
N
Department of Pharmacology, Umeå University, Sweden.
Uhlén
S
S
Wikberg
J E
JE
D000818:Animals; D001667:Binding, Competitive; D004146:Dioxanes / Q000378:metabolism; D006168:Guinea Pigs; D019329:Idazoxan; D007093:Imidazoles / Q000378:metabolism*; D054755:Imidazoline Receptors; D007700:Kinetics; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008954:Models, Biological; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism*; D014316:Tritium
D004146:Dioxanes; D007093:Imidazoles; D054755:Imidazoline Receptors; D011942:Receptors, Adrenergic, alpha; D011955:Receptors, Drug; D014316:Tritium; C041255:detomidine; D019329:Idazoxan