DETOMIDINE BINDING TO GUINEA-PIG LIVER IMIDAZOLINE RECEPTORS (I-RECEPTORS) SHOWS MARKED POSITIVE COOPERATIVITY

The binding of [H-3]-idazoxan to guinea Pig liver membranes was measur ed in the presence of 3 muM rauwolscine, which prevented the binding [ H-3]-idazoxan to alpha2-adrenergic receptors. Under these conditions t he radioligand bound to saturable imidazoline receptors (1-receptors) with a K(d) of 18 nM and a B(max) of 665 fmol mg-1 protein. Six drugs which were used to compete for [H-3]-idazoxan in the liver caused comp etition curves of widely varying steepness. Fitting the competition cu rves to the standard four parameter logistic function showed that the Hill coefficients (n(H)) varied from 2.02 (detomidine) to 0.43 (UK-14, 304), The n(H)'S obtained in liver for the six compounds correlated st rongly (r=0.99; P < 0.001) with the corresponding n(H)'S obtained in a previous study on the guinea pig kidney where the drugs were also tes ted in competition with [H-3]-idazoxan (Wikberg et al. 1992). Good cor relation was also found for the Log(K(i)) values of drugs determined i n the two tissues (r=0.96; P<0.005). Whereas the standard logistic fun ction accurately described the competition curves of the 5 drugs teste d in the liver for which the competition curve Hill coefficients varie d between 0.43 to 1.41 (UK-14,304, rilmenidine, histamine and d- and 1 -medetomidine), it did not accurately fit the detomidine competition c urves. Instead the detomidine competition curves could be more accurat ely described by a model composed of the sum of two independent logist ic functions. Using this model detomidine appeared to compete with [H- 3]-idazoxan with two apparent affinity components, one with a K(i) of 0.26 muM and an n, of 3.24 and the other with a K(i) of 4.9 muM and an n(H) of 1.09. The proportion of the affinity components were 72% of t he higher and 28% of the lower affinity. The data are discussed with t he notion that guinea pig liver and kidney I-receptors are similarly r egulated by both positive and negative allosteric cooperative interact ions.