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1Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1; 3Department of Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada H3C 3J7; and 2Department of Bioengineering, University of California, San Diego, La Jolla, California 92093-0412
Submitted 16 September 2003 ; accepted in final form 28 December 2003
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.
C receptor; calcium current; hyperpolarization-activated current
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