Effect Of C-type Natriuretic Peptide On Atrial Dynamics And Cyclic Nucleotide Concentration In Beating Rabbit Atria

C-type natriuretic peptide (CNP) is a third member of natriuretic peptides family (NPs). The molecule incorporates a 17-residue intra-molecular disulfide loop, common to all natriuretic peptides. CNP was first described in central nervous systems where it occurs in greater concentrations. Recently, it has been demonstrated that the distribution of CNP is wide and immunoreactivity has been found in kidney, intestines, lung, and cardiacvascular system and therefore could allow CNP important roles in variety of pathologies. The previous reports had shown that CNP decreased cardiac filling pressure, cardiac output, and arterial blood pressure concomitantly with increased cGMP levels. There has been some in vitro work with heart that suggest CNP-induced Ca~2+ influx in single atrial myocyte with dose-dependent manner and positive chronotropic and inotropic effects in dog heart. These data suggests that the roles of CNP on the cardiac dynamics mediated by GC-cGMP signaling, but the effect of CNP on cardiac dynamis is controversy. The intracellular cyclic nucleotide is determined both by the rate of cyclic nucleotide generation by cyclase and its degradation by phosphodiesterases (PDEs). It is likely that control of the degradation of cyclic nucleotide is of fundamental importance in the regulation of cellular responses. At least four families of PDEs, PDE1, PDE2, PDE3, and PDE4, were identified in the heart. PDE2 and PDE3 witch have controlled by intracellular cGMP levels. However, their respective roles are not well understood in the cardiac atrium. Their for the present study was to define the roles of CNP and PDE subtypes, PDE2 and PDE3 on the atrial dynamics and regulation of intracellular cGMP, and cAMP levels in beating rabbit perfuesd atria under basal and adenylyl cyclase (AC) activated conditions. CNP inhibited atrial dynamics with an increase in cGMP but not cAMP production in dose-dependent manner in a basal condition. In contrast, in a condition of AC activation withforskolin, CNP augmented the stimulated atrial contractility concomitantly with a further increase in cAMP productions. The augmentation of the stimulated contractility was reversed and the augmented cAMP increase was blockade by the combined treatment with an ibhibitor of cGMP-inhibited phosphodiesterase (PDE3), milrinone or cilotamide. An inhibitor of cGMP-stimulated phosphodiesterase (PDE2), erythro-9-(2-Hydroxy-3-nonyl) adenine-HCI (EHNA), attenuated the CNP-induced inhibition in atrial contractility in the presence or absence of forskolin plus milrinone (or cilostamide). These data suggest that: 1) CNP inhibited atrial dynamics with an increase in cGMP but not cAMP production in dose-dependent manner in a basal condition via GC-cGMP signaling. 2) In a condition of AC activation with forskolin, CNP augmented the stimulated atrial contractility concomitantly with a further increase in cAMP productions. 3) GC-cGMP-PDE signaling pathway involved in effect of CNP on atrial dynamics and cAMP production under basal and AC activated conditions.