CONTRACTION OF THE GUINEA-PIG ISOLATED, PERFUSED TRACHEA TO PURINE AND PYRIMIDINE AGONISTS

Unlike methacholine and histamine, ATP and uridine 5'-triphosphate (UT P) are more potent contractile agonists when they are applied to the m ucosal (intraluminal, IL) surface of the guinea pig perfused trachea t han when they are applied to the serosal (extraluminal, EL) surface. T he relative contractile activities of a series of purine and pyrimidin e compounds were assessed. The order of EL activity was: [2-methythio ATP (2 MeSATP) = adenosine 5'-diphosphate (ADP)] > [adenosine 5'-O-(2- thiodiphosphate) (ADP beta S)= ATP = adenosine 5'-O-(3-thiotriphosphat e) (ATP gamma S)] > [(beta,gamma-imido ATP) (APPNP)= alpha, beta-methy lene ATP (APCPP)] > [UTP = uridine 5'-diphosphate (UDP) = inosine 5'-t riphosphate (ITP)] > [xanthosine 5'-triphosphate (XTP) beta,gamma-meth ylene ATP (APPCP)]. EL adenosine, adenosine 5'-monophosphate, uridine 5'-monophosphate and uridine were weak or inactive. The EL order of ac tivity, therefore, shares some characteristics of P-2Y receptors. The order of IL activity was: (ATP = UTP = ITP)> (ATP gamma S = ADP = APPN P = 2 MeSATP)> (UDP = ADP beta S = XTP)> APCPP; the other compounds we re weak or inactive. The IL order of activity, therefore, resembled th at for P-U or ''nucleotide receptors.'' ATP, APPNP, UTP, UDP, ITP and XTP were more active when added to the IL than after administration to the EL bath; the remaining compounds were similarly active EL and IL, or were more active EL than IL. Greater IL than EL activity of agonis ts was a property associated with preference for P-2U-receptors. The E L and IL activities of the agonists compare favorably with those repor ted for basolateral and apical stimulation of short circuit current an d [Ca++](i) of human respiratory epithelium, and phospholipase C activ ation of cultured human airway epithelium.