Contractile effects of nucleotides in guinea pig isolated, perfused trachea: involvement of respiratory epithelium, prostanoids and Na+ and Cl- channels

Abstract

ATP and UTP contracted guinea pig isolated, perfused trachea and were more potent when applied to the mucosal (intraluminal, IL) surface than when applied to the serosal (extraluminal, EL) surface. IL ATP and IL UTP were equipotent (ATP approximately UTP); EL ATP was 7-fold more potent than EL UTP (ATP > UTP). beta, gamma-Methylene ATP was nearly devoid of activity. Epithelium (Epi) removal decreased IL ATP potency and EL and IL maximum response magnitude, but elevated the IL UTP maximum response. In the presence of EL and IL indomethacin (3 x 10(-6) M; +/- Epi) to inhibit cyclo-oxygenase, or beta, gamma-methylene ATP (10(-4) M) to desensitize receptors, contractions to ATP were abolished, but those to UTP were not. Cl- channel blockade with 4,4'-diisothiocyano-2,2'-stilbene disulfonate (DIDS; 10(-4) M; +/- Epi) and sodium channel blockade with amiloride (10(-4) M; +/- Epi) antagonized contractions to EL and IL ATP and UTP. DIDS and amiloride did not inhibit contractions to methacholine; IL reactivity to methacholine was potentiated by indomethacin and Epi removal. Our findings indicate that the Epi facilitates contraction to ATP, which involves an atypical P2 purinoceptor, prostanoids, and Na+ and Cl- channels. Contractile responses to UTP involve a different receptor, and are neither facilitated by the Epi nor mediated by prostanoids, but involve these channels.