Detomidine Binding to Guinea Pig Liver Imidazoline Receptors (I‐Receptors) Shows Marked Positive Cooperativity

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Abstract
The binding of [3H]‐idazoxan to guinea pig liver membranes was measured in the presence of 3 μM rauwolscine, which prevented the binding [3H]‐idazoxan to α2‐adrenergic receptors. Under these conditions the radioligand bound to saturable imidazoline receptors (I‐receptors) with a Kdof 18 nM and a Bmaxof 665 fmol mg‐1protein. 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 (Wikberget 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 1‐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. Using this model detomidine appeared to compete with [3H]‐idazoxan with two apparent affinity components, one with a Kiof 0.26 μM and an nHof 3.24 and the other with a Kiof 4.9 μM and an nHof 1.09. The proportion of the affinity components were 72% of the higher and 28% of the lower affinity. The data are discussed with the notion that guinea pig liver and kidney I‐receptors are similarly regulated by both positive and negative allosteric cooperative interactions.

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