Inhibitors of spasmogen‐induced Ca 2+ channel suppression in smooth muscle cells from small intestine

1 Whole‐cell patch‐clamp recordings were made from smooth muscle cells isolated from the longitudinal muscle layer of guinea‐pig ileum. Carbachol (acting at muscarinic receptors) or histamine (acting at H 1 histamine receptors) suppressed Ca 2+ channel current. The effect of either agonist had an initial transient component followed by a sustained component. 2 Wortmannin inhibited transient and sustained components of carbachol‐induced Ca 2+ channel current suppression: half‐effective inhibitory concentrations (IC 50 ) were 1.1 μ M and 0.6 μ M for the two components respectively. Wortmannin also inhibited the transient phase of carbachol‐induced cationic current (IC 50 1.6 μ M ) and Ca 2+ ‐dependent K + ‐current (IC 50 1.7 μ M ). Wortmannin did not appear to produce any direct block of cationic channels or Ca 2+ channels. 3 Intracellular application of the phospholipase inhibitor D609 (tricyclodecan‐9‐ylxanthogenate) inhibited transient and sustained components of histamine action on the Ca 2+ channel current: the IC 50 was about 130 μ M for both components. Carbachol action on Ca 2+ channels was also inhibited by D609. D609 had no significant direct blocking effect on Ca 2+ channels, cationic channels activated by carbachol, or Ca 2+ ‐activated K + ‐current in response to flash‐photolysis of caged‐inositol 1,4,5‐trisphosphate. 4 Micromolar concentrations of wortmannin and D609 are inhibitors of both components of spasmogen‐induced Ca 2+ channel suppression. The data suggest that both components are mediated by a common, or similar, signal transduction element which is a phospholipase C (PLC) or phospholipase D (PLD) isoform.British Journal of Pharmacology (1998) 125 , 667–674; doi: 10.1038/sj.bjp.0702112