PROSTAGLANDINS

A COMPARISON OF LFUKOTRIENE ACTIVITY ON GUINEA-PIG LUNG USING FUNCTIONAL AND RADIOLIGAND BINDING STUDIES.

Peter Norman, Trevor S. Abram, NigeZ J. Cuthbert and Phillip J. Gardiner. Research Department, Miles Laboratories Limited, Stoke Court, Stoke Poges, SL2 4LY, Buckinghamshire, United Kingdom.

The interaction of a radioligand with a physiologically relevant receptor is confirmed by a number of criteria one of which is agonist specificity. The order of potency of the agonists in

eliciting the biological response should correlate with their order of potency in competing for the binding site. We have isolated a membrane fraction from guinea-pig lung and demonstrated that 3H-LTDq specifically binds to this membrane with a K of 0.85nM and has the characteristics of a homogenous receptor popElation (1).

We investigated the inhibitory activity of a range of leukotriene and non-leukotriene like structures on the membrane receptor fraction and compared our data with functional studies using guinea-pig isolated lung strips (2),

Of the agonists tested in the binding studies LTB,,, histamine, and U46619 (a thromboxane receptor mimetic) showed little or no

PGF2ff

inhibitory activity. ,In contrast the remaining agonists displaced 'H-LTD,, with the following rank order of potency (Ki, nM) LTD4 (1.08) > LTE$ (2.0) > 11-trans LTD4 (3.1) > 11-trans LTE,, (14.7) >> LTC4 (390.0).

In the functional studies all agonists contracted the preparations however LTB4 responses were prone to tachyphylaxis and not dose

related. The following rank order of potency was obtained (relative potency) LTD,, (1.0) > ll-trans LTD4 (1.9) > LTC,, (7.6) > LTE4 (8.3)

> U46619 (40.8) >>> Histamine (212.0).

Our results suggest that the membrane receptor fraction shows selectivity for peptido-leukotrienes. However, the poor correlation with regards LTC* activity in the two systems suggests that at least one other leukotriene receptor exists on this tissue.

1) Abram, T., Norman, P. and Barnes, IUPHAR.

2) Lullich, K.M., Mitchell, M.W. and Br.J.Pharmacol., 58: 71.

P. (1984) Abstract 1332

Sparrow, M.P. (1976)

640 NOVEMBER 1984VOL.28NO.S