EPITHELIUM MODULATES THE KINETICS OF THE RESPONSE TO SUBSTANCE-P AND ITS INTRINSIC ACTIVITY IN THE GUINEA-PIG TRACHEA

The contractile response of guinea-pig tracheal preparations with or w ithout epithelium to substance P has been studied in the presence or a bsence of thiorphan, an endopeptidase 24.11 inhibitor, paying special attention to the kinetics of the response. Without thiorphan, the resp onse to substance P was greater in tracheal preparations without epith elium than in tracheal preparations with epithelium. The concentration -response curve was shifted to the left in the absence of the epitheli um. In the presence of 10 mu M thiorphan, the maximal contractile resp onse induced by single doses of substance P (0.1 to 10 mu M) was lower in tracheal preparations without epithelium. The maximal responses re quired 10 min in tracheal preparations with epithelium and 2 min in tr acheal preparations without epithelium. These epithelium-dependent dif ferences of reactivity remained in the presence of lipoxygenase or cyc looxygenase inhibitors and of selective antagonists of muscarinic, ser otoninergic and histaminergic receptors, after the pre-treatment of ti ssues with capsaicin or compound 48/80 and in the presence of tetrodot oxin. The profile of the cumulative concentration-response curves for substance P was largely dependent on the time between two successive d oses. When this time was short (2-4 min), curves established with or w ithout the epithelium were parallel and both reached similar maximal v alues (2696 +/- 214 mg and 2780 +/- 62 mg, respectively). The curve in tracheal preparations without epithelium was slightly shifted to the left (EC(50s): 24 +/- 10 nM and 78 +/- 19 nM). When this time was long er (10 min, ie corresponding to the time required for a full response to a single dose in intact trachea) the potency of substance P was not modified (EC(50s): 13 +/- 3 nM and 52 +/- 11 nM), but a lower maximal response was observed with tracheal preparations without epithelium ( 1440 +/- 182 mg and 2832 +/- 209 mg). Similar results were observed wi th neurokinin A and neurokinin B. Thus, the removal of the epithelium led to a more rapid contraction and to a decrease of the maximal respo nse to neurokinins, ie a decreased intrinsic activity, a property know n to be drug- and tissue-dependent. These data suggest that the intrin sic activity of drugs depends on the cellular environment of the targe t cells in a tissue and is partly related to the diffusion and metabol ism of drugs and to drug-induced hyporeactivity of the target cells.