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1 Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
2 Department of Physiology, University of Montreal, Montreal, Quebec, Canada
3 Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Department of Bioengineering, University of California, San Diego, La Jolla, USA
* To whom correspondence should be addressed. E-mail: wgiles{at}ucalgary.ca.
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 the mouse heart. The selective NPR-C receptor agonist, cANF (10-7 M), significantly decreased heart rate in the presence of isoproteronol (5 x 10-9 M), as indicated by an increase in R-R interval of electrocardiograms obtained from Langendorff perfused hearts. Voltage clamp measurements in enzymatically isolated single pacemaker myocytes revealed that both CNP (10-8 M) and cANF (10-8 M) significantly inhibited the L-type calcium current, ICa(L). These findings suggest that the CNP effect on this current is mediated by the NPR-C receptor. 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 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) since the hyperpolarization-activated current, If, was unaffected by either 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 the NPR-C receptor and reducing ICa(L) through the coupling to Gi protein.
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