Effects of C-type natriuretic peptide on ionic currents in mouse sinoatrial node: a role for the NPR-C receptor

Abstract

The effects of C-type natriuretic peptide (CNP) on heart rate and ionic currents were demonstrated by recording the ECG from adult mice and performing voltage-clamp experiments on single sinoatrial (SA) node cells isolated from mouse heart. The selective natriuretic peptide type C receptor (NPR-C) agonist cANF (10(-7) M) significantly decreased heart rate in the presence of isoproterenol (5 x 10(-9) M), as indicated by an increase in the R-R interval of ECGs obtained from Langendorff-perfused hearts. Voltage-clamp measurements in enzymatically isolated single pacemaker myocytes revealed that CNP (10(-8) M) and cANF (10(-8) M) significantly inhibited L-type Ca2+ current [ICa(L)]. These findings suggest that the CNP effect on this current is mediated by NPR-C. Further support for an NPR-C-mediated inhibition of ICa(L) in SA node myocytes was obtained by altering the functional coupling between the G protein Gi and NPR-C. In these experiments, a "Gi-activator peptide," which consists of a 17-amino acid segment of NPR-C containing a specific Gi protein-activator sequence, was dialyzed into SA node myocytes. This peptide decreased ICa(L) significantly, suggesting that NPR-C activation can result in a reduction in ICa(L) when CNP is bound and the Gi protein pathway is activated. This effect of CNP appears to be selective for ICa(L), because the hyperpolarization-activated current was unaffected by CNP or cANF. These results provide the first demonstration that CNP has a negative chronotropic effect on heart rate and suggest that this effect is mediated by selectively activating NPR-C and reducing ICa(L) through coupling to Gi protein.

Osteocrin Is a Specific Ligand of the Natriuretic Peptide Clearance Receptor That Modulates Bone Growth

“…6). NPR-C-specific ligand binding has been demonstrated to inhibit adenylate cyclase (53,54) and modulate ion channel activity (55,56). Thus, the discovery of an endogenous and specific ligand for NPR-C may have further significance beyond just quenching of NPR-Cs clearance function.…”

Functional characterization of cardiac progenitor cells and their derivatives in the embryonic heart post‐chamber formation

“…Indeed, the E11 ventricular myocardium has been shown to express high levels of NOS and cGMP proteins compared to the E16 myocardium (Ji et al, 1999) and also to respond to muscarinic and adrenergic stimulation . Activation of NPR-C was shown to significantly inhibit ISO induced Ltype Ca 2þ current (LTCC) via the Gi pathway in adult SA nodal, atrial, and ventricular myocytes (Rose et al, 2003(Rose et al, , 2004(Rose et al, , 2005 (Fig. 7A).…”

Culture and adenoviral infection of sinoatrial node myocytes from adult mice

“…SAMs were isolated from the sinoatrial node, which was defined as the region bordered by the crista terminalis, the interatrial septum, and the superior and inferior vena cavae as in previous studies (16,18,38,14,25,33). Individual cells were initially identified visually by the presence of spontaneous contractions and by their characteristic morphology, small size, and lack of striations as we have previously described (14,16,18,38).…”