Proceedings of the British Thoracic Society. 12-14 July 1989, University of Southampton. Abstracts.

Receptor mediated hydrolysis of phos- phatidylinostol 4,5-bisphosphate is now regarded as an important step in the regulation of intracellular calcium and ASM contraction.Lithium (Li +), a potent inhibitor of inositol-l-phosphatase, depletes cellular inositol and has been shown to modulate ASM contraction in vitro (Menkes et al, Am Rev Respir Dis 1988;33:A1 15).We have therefore examined the effects ofLi + on musarinic receptor stimulated inositol polyphosphate (InsPl-InsP4) formation in bovine trachealis.Muscle slices (300 x 300 pm) were labelled with[3H]myo-inositol (NEN; 2 5 pCi/50 p1 slices) prior to stimula- tion with 01 mM carbachol for 30 min in the presence or absence of Li+.Reactions were terminated with 1M TCA and Inspl-InsP4 separated by anion exchange chromatogra- phy.Li + caused a dose dependent increase in [3H] InsPl accumulation (10-7 (1-3) fold increase (mean (SEM)); EC50 1-7 mM). 5 mM Li + increased [3H] InsP 2, [3H] InsP3 and [3H] InsP4 levels by 2-1 (01), 1-2 (01) and 0-98 (04) fold respectively.The inhibition of [3H] InsP2 breakdown by Li + was less potent than for [3H] InsPl.The effect of Li + on [3H] InsP3 accumulation may reflect the marked predominance of the Ins (1, 3, 4)P3 isomer over Ins (1, 4, 5)P3 seen in this tissue following carbachol stimulation since the conversion of Ins (1, 3, 4)P3 to Ins (3, 4)P2 is also Li+ sensitive.This study indicates that low concentrations of Li + severely perturb carbachol stimulated inositol polyphosphate metabolism in ASM.These findings, together with the depletion in phos- phatidylinositol seen following carbachol stimulation in the presence of Li + (Chilvers et al, Br J Pharmac: 1988;95:778P), may form the biochemical basis for the effect of lithium on ASM contractility.Tolerance to metabisulphite induced bronchoconstriction and duration of action of nedocromil sodium