EFFECTS OF OKADAIC ACID ON THE HUMAN ISOLATED BRONCHUS

The effects of okadaic acid, a polyether derivative of a 38-carbon mon ocarboxylic fatty acid obtained from a culture of the marine dinoflage llate, Prorocentrum lima, were studied on the human isolated bronchus. In low concentrations (0.01 and 0.03 mu M), okadaic acid had no signi ficant effect of its own on the human isolated bronchus, but in higher concentrations (0.1-10 mu M) it induced a series of contractions and relaxations. The first contraction was of low intensity (5% of maximum response to acetylcholine 3 mM) and occurred early. The second contra ction had a higher amplitude (30% of maximum response to acetylcholine 3 mM) and reached its peak with okadaic acid 0.3 mu M. At higher conc entrations (1-10 mu M), following a relaxation phase, a later rebound contraction occurred between 70 and 120 min and corresponded to 40% of the maximum response to acetylcholine 3 mM. In addition, okadaic acid inhibited or abolished the contractile response evoked by either KCl 60 mM or acetylcholine 3 mM with IC50 of 0.04 and 0.12 mu M, respectiv ely. The second contraction evoked by 0.3 mu M okadaic acid was partia lly inhibited in the presence of the Ca2+ channel blocker, nicardipine 1 mu M, or after incubation of the human bronchus in a Ca2+-free solu tion and it was completely abolished in the presence of CdSO4 0.1 mM. The non-specific smooth muscle relaxant, papaverine (1-15 mu M), inhib ited the second contractile response to okadaic acid 0.3 mu M in the w ay it inhibited the KCI 60 mM- or the acetylcholine 3 mM-induced respo nse. In contrast, caffeine (0.1-10 mM) inhibited or almost completely abolished this okadaic acid 0.3 mu M-induced contraction at concentrat ions at which it failed to modify significantly or induced only a part ial inhibition of the contractile responses to KCI 60 mM or acetylchol ine 3 mM. Okadaic acid 1 mu M did not affect the intracellular levels of phosphoinositides in the human isolated bronchus. To conclude, thes e results show that okadaic acid induces complex contractile and relax ant effects on the human isolated bronchus. Its contractile effect is independent of the phosphoinositide pathway; it seems to involve, at l east partially, entry of Ca2+ into the cell and mobilization of intrac ellular Ca2+ from a caffeine-dependent pool, but other mechanisms may also be acting.