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 na triuretic peptides. were investigated in epithelium-denuded guinea pig trac heal rings, treated with indomethacin (5 muM) and phosphoramidon (1 muM) an d contracted with histamine (3 muM). Atrial natriuretic peptide (ANP) was a more potent relaxant than C-type natriuretic peptide whereas ANP-(4-23) wa s inactive suggesting the involvement of ANP(A) receptors in the relaxant e ffect 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 rel axant response to sodium nitroprusside. The relaxant response to ANP was no t altered by ODQ demonstrating the involvement of particulate guanylyl cycl ase. ANP-induced relaxations, as well as sodium nitroprusside-induced relax ations, were similarly potentiated by rolipram (4-(3-(cyclopentyloxy)-4-met hoxyphenyl)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 glib enclamide (10 muM), a selective blocker of ATP-sensitive K+ channels, and b y 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 acti vation 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 airwa y smooth muscle. However, relaxations to forskolin and to isoproterenol wer e not altered in the presence of ANP-(4-23) or ANP demonstrating that the i nhibitory effect of ANP-(4-23) and ANP on adenylyl cyclase was not sufficie nt to alter the functional response induced by these two activators of aden ylyl cyclase. (C) 2001 Elsevier Science B.V. All rights reserved.