| As an endocrine gland, the heart synthesis and secretion of natriureitc peptides (NPs) include atrial natriureitc peptide (ANP), brain ntriuretic peptide (BNP), C-type natriuretic peptide (CNP) and dendroaspis natriuretic peptide (DNP). These hormones elicit natriuretic, diuretic, hypotensive effects, regulate body fluid and blood pressure.CNP, a third member of the NPs, was first isolated from the porcine brain and recognized that it was a neuropeptide, and late, it was demonstrated that the distribution of CNP was wide and immunoreactivity has been found in kidney, intestines, lung, and cardiovascular system. Therefore, it was indicated that several tissues could synthesis and release of CNP. Because the plasma levels of CNP are very low, the presence of the peptide in tissues is considered to perform a paraceine/autocrine function as a local regulator. CNP has been shown to produce a variety of effects including vascular dilation, antiproliferative and antimigative effects on vascular smooth muscle cells, reduce to form of arteriosclerosis and plaque, and inhibition of remodeling and inflammatory reaction.Recently, a regulatory function of CNP has been recognized in the hart, i. e., CNP-induced negative and/or positive inotropic effects in the heart. However, the effects and the mechanism of the CNP on the heart are not well known. Therefore, the purpose of the present study was to define the effects of CNP on atrial dynamics and regulatory roles of intracellular cGMP and cAMP levels in perfused beating atria.The results of the present study were shown that:1. Effect of CNP on atrial dynamics1) Different doses of CNP (10.0 nmol/L,30.0 nmol/L and 300.0 nmol/L) significantly inhibited atrial stroke volume and pulse pressure (P＜0.05 and P＜0.01 vs control) in dose dependent manner.2) CNP (30.0 nmol/L) increased atrial cGMP production (P＜0.001 vs control) and decreased atrial stroke volume and pulse pressure (both P＜0.01 vs control) without changes in atrial cAMP levels (P>0.05 vs control). 3) CNP-induced increase of atrial cGMP was blocked by HS-142-1, an inhibitor of NPR-B receptor.2. Effects of subtype phosphodiesterase on CNP-induced atrial dynamics1) 3-Isobutyl-l-methylxanthine (IBMX,1.0 mmol/L), a non-specific inhibitor of phosphodiesterses (PDEs) significantly increased atrial stroke volume, pulse pressure, cAMP and cGMP levels (all P＜0.001 vs Control). In the presence of IBMX, CNP (30.0 nmol/L) failed to modulation of IBMX-induced increase of atrial dynamics and cyclic nucleotides (P＜0.001 vs control and P＞0.05 vs the period of second cycle treated with IBMX alone).2) [erythro-9-(2-Hydroxy-3-nonyl) adenine-HCl] (EHNA,0.1 mmol/L), a specific inhibitor of PDE2, decreased atrial dynamics (P＜0.05 vs control) with increased atrial cAMP levels (P<0.05 vs control). In the presence of EHNA, CNP (30.0 nmol/L) augmented the effects of EHNA-induced decrease of atrial dynamics (P＜0.01 vs the period of third cycle treated with EHNA alone) and the EHNA-induced increase of atrial cAMP levels (P＜0.05 vs the period of third cycle treated with EHNA alone). However, EHNA+CNP attenuated inhibitory effect of CNP the atrial dynamics.3) Milrinone (10.0μmol/L), a specific inhibtor of PDE3, significantly increased atrial cAMP levels (P<0.05 vs control) without changes in atrial dynamics and cGMP levels. In the presence of milrinone, CNP (30.0 nmol/L) significantly decreased atrial dynamics (P＜0.001 vs control) with increased cGMP levels (P＜0.001 vs control).3. Effects of forskolin on CNP-induced atrial dynamics1) Forkolin (0.1μmol/L), an activator of adenylyl cyclase (AC), reversed the inhibitory effects of CNP (30.0 nmol/L) on atrial dynamics and sacrificed the CNP play a positive inotropism via an augmented increase in atrial cAMP levels.2) In the presence of forskolin, the augmented increase of atrial dynamics and c AMP levels by CNP were blockade by combined treatment with mirinone, an inhibitor of PDE3, and recovered the inhibitory effect of CNP on atrial dynamics again.3) In the presence of forskolin and milrinone, the augmented increase of atrial dynamics and cAMP levels by CNP were blockade by combined treatment with EHNA (0.1 mmol/L), and the inhibitory effect of CNP on atrial dynamics also attenuated by EHNA. 1) CNP (0.5μmol/L) also inhibited rat atrial dynamics.2) Forskolin (7.0μmol/L) also reversed inhibitory effect of CNP on rat atrial dynamics and then CNP augmented rat altrial dynamics.3) PDE3A gene expression was decreased by CNP and increased by forskolin respectively. In the presence of forskolin, the PDE3A gene expression was also decreased by combined treatment of CNP.The results of the present study indicate that:1. CNP inhibits atrial dynamics via GC-cGMP signaling in beating rabbit atria.2. Subtype of PDEs show the distinct roles in regulation of atrial dynamics with CNP.3. In the presence and absence of forskolin, CNP can play positive and/or negative inotropic effects on atrial dynamics via GC-cGMP-PDE signaling pathway.
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