RT Journal Article
SR Electronic
T1 The extracellular cAMP - adenosine pathway in airway smooth muscle
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.118.247734
DO 10.1124/jpet.118.247734
A1 Enio Setsuo Arakaki Pacini
A1 Sarah Sanders-Silveira
A1 Rosely Oliveira Godinho
YR 2018
UL http://jpet.aspetjournals.org/content/early/2018/04/23/jpet.118.247734.abstract
AB In the respiratory tract, intracellular cAMP has a key role in the smooth muscle relaxation induced by β2-adrenoceptors/Gs protein/adenylyl cyclase axis. In other tissues, cAMP also works as an extracellular messenger, after its efflux and interstitial conversion to adenosine by ectoenzymes. The aim of this study was to identify cAMP efflux and "extracellular cAMP-adenosine pathway" in the airway smooth muscle. Firstly, we tested the ability of β2-adrenoceptor agonists formoterol or fenoterol to increase the extracellular cAMP in isolated tracheal rings from adult male Wistar rats. The effects of adenosine, cAMP, 8-Br-cAMP, fenoterol or formoterol were also evaluated in the isometric contraction of control or carbachol (CCh) precontracted tracheas, normalized as percentage of CCh-induced response. Fenoterol and formoterol induced 70-80% relaxation and increased by up to 280-450% the extracellular cAMP levels. While exogenous cAMP or adenosine evoked phasic contractions, the membrane-permeable cAMP analog 8-Br-cAMP induced relaxation of CCh-precontracted tracheas. The simultaneous inhibition of adenosine degradation/ uptake with EHNA plus uridine increased by 3-fold the maximum cAMP-induced contraction, whereas it was significantly reduced by AMPCP (ecto-5’-nucleotidase inhibitor), and by adenosine receptor antagonists CGS-15943 (non-selective) or DPCPX (A1-selective). Finally, CGS-15943 shifted to the left the concentration-relaxation curve for fenoterol. In conclusion, our results show that airway smooth muscle expresses the “extracellular cAMP-adenosine pathway” associated with contracting effects mediated by A1 receptors. The cAMP efflux triggered by fenoterol/formoterol indicates that the extracellular cAMP-adenosine pathway may play a role in balancing relaxant effects of β2-adrenoceptor agonists in airways, which may impact their bronchodilation effects.