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 without epithelium to substance P has been studied in the presence or absence of thiorphan, an endopeptidase 24.11 inhibitor, paying special attention to the kinetics of the response. Without thiorphan, the response to substance P was greater in tracheal preparations without epithelium than in tracheal preparations with epithelium. The concentration-response curve was shifted to the left in the absence of the epithelium. In the presence of 10 microM thiorphan, the maximal contractile response induced by single doses of substance P (0.1 to 10 microM) was lower in tracheal preparations without epithelium. The maximal responses required 10 min in tracheal preparations with epithelium and 2 min in tracheal preparations without epithelium. These epithelium-dependent differences of reactivity remained in the presence of lipoxygenase or cyclooxygenase inhibitors and of selective antagonists of muscarinic, serotoninergic and histaminergic receptors, after the pre-treatment of tissues with capsaicin or compound 48/80 and in the presence of tetrodotoxin. The profile of the cumulative concentration-response curves for substance P was largely dependent on the time between two successive doses. When this time was short (2-4 min), curves established with or without the epithelium were parallel and both reached similar maximal values (2696 +/- 214 mg and 2780 +/- 62 mg, respectively). The curve in tracheal preparations without epithelium was slightly shifted to the left (EC50s: 24 +/- 10 nM and 78 +/- 19 nM). When this time was longer (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 (EC50s: 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 with neurokinin A and neurokinin B. Thus, the removal of the epithelium led to a more rapid contraction and to a decrease of the maximal response to neurokinins, ie a decreased intrinsic activity, a property known to be drug- and tissue-dependent. These data suggest that the intrinsic activity of drugs depends on the cellular environment of the target cells in a tissue and is partly related to the diffusion and metabolism of drugs and to drug-induced hyporeactivity of the target cells.