Relaxation and modulation of cyclic AMP production in response to atrial natriuretic peptides in guinea pig tracheal smooth muscle

Relaxation and modulation of cyclic AMP production in response to atrial natriuretic peptides. were investigated in epithelium-denuded guinea pig tracheal rings, treated with indomethacin (5 muM) and phosphoramidon (1 muM) and contracted with histamine (3 muM). Atrial natriuretic peptide (ANP) was a more potent relaxant than C-type natriuretic peptide whereas ANP-(4-23) was inactive suggesting the involvement of ANP(A) receptors in the relaxant effect of ANP. ODQ (1H-[1,2,4]oxadiazolo[4,3-A]quinoxalin-1-one, 10 muM), a selective inhibitor of soluble guanylyl cyclase, markedly inhibited the relaxant response to sodium nitroprusside. The relaxant response to ANP was not altered by ODQ demonstrating the involvement of particulate guanylyl cyclase. ANP-induced relaxations, as well as sodium nitroprusside-induced relaxations, were similarly potentiated by rolipram (4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one, 3 muM), a type IV phosphodiesterase inhibitor, and by zaprinast (2-(2-propyloxyphenyl)-8-azapurin-6-one, 10 muM), a type V phosphodiesterase inhibitor. ANP-mediated response was unaffected by glibenclamide (10 muM), a selective blocker of ATP-sensitive K+ channels, and by apamin (1 muM), a selective blocker of small-conductance Ca2+-activated K+ channels. Iberiotoxin (100 nM) extensively Ca2+-activated K+ channels. In addition, ANP (10 prevented the relaxant effect of ANP suggesting the activation of large-conductance Ca2+ nM) and ANP-(4-23) (100 nM) significantly reduced forskolin (1 muM)-stimulated cAMP accumulation suggesting, for the first time, the presence of functional ANP(C) receptors in guinea pig airway smooth muscle. However, relaxations to forskolin and to isoproterenol were not altered in the presence of ANP-(4-23) or ANP demonstrating that the inhibitory effect of ANP-(4-23) and ANP on adenylyl cyclase was not sufficient to alter the functional response induced by these two activators of adenylyl cyclase. (C) 2001 Elsevier Science B.V. All rights reserved.