Contractile effects of nucleotides in guinea pig isolated, perfused trachea: involvement of respiratory epithelium, prostanoids and Na+ and Cl- channels.
The contractile effects of ATP, beta-gamma-methylene-adenosine- triphosphate (APPCP) and uracil-triphosphate (UTP) in guinea pig isolated, perfused trachea were compared. Segments of guinea-pig trachea were isolated, mounted to perfusion holders, and connected to pressure transducers via side hole catheters. The pressure differences caused by the various agonists were measured and used to generate concentration response curves. The inhibitors included indomethacin, a cyclooxygenase inhibitor; amiloride, a sodium channel blocker; and APPCP, a P2X receptor agonist. ATP added to control tracheas caused contraction in lower concentrations and relaxation in higher concentrations. Of the nucleotides studied, ATP caused the highest increase in extraluminal (EL) contractile activity, followed by UTP, with APPCP the weakest. In the intraluminal (IL) bath, ATP and UTP were equivalent. The high potency of IL ATP, combined with the decreased potency of ATP in epithelium denuded trachea, suggested that the epithelium facilitated responses to ATP. Contractions to ATP ceased in the presence of indomethacin, with or without the epithelium present. When APPCP was added to the trachea baths, contractions to IL ATP ceased, yet responses to UTP were not affected. 4,4-Diisothiocyano- 2,2-stilbene-disulfonate (DIDS) and amiloride reduced contractions to both ATP and UTP, either with or without the epithelium present. When DIDS and amiloride were applied simultaneously, ATP induced contractions ceased. Neither DIDS nor amiloride affected methacholine induced contractions, suggesting that the two inhibitors specifically depressed nucleotide induced contractions. The authors conclude that the epithelium facilitates contractile responses to ATP, and that these responses involve the production of ion channels. A separate receptor assists contractions caused by UTP, since the inhibition of ATP and UTP often differed. Contractions caused by ATP are mediated by prostanoids, considering that indomethacin abolished contractions.