부산대학교 도서관

Background and Purposes Myocardial C-type natriuretic peptide ( CNP) levels are increased in heart failure. CNP can induce negative inotropic ( NIR) and positive lusitropic responses ( LR) in normal hearts, but its effects in failing hearts are not known. We studied the mechanism of CNP-induced NIR and LR in failing hearts and determined whether sarcoplasmatic reticulum Ca2+ ATPase2 ( SERCA2) activity is essential for these responses. Experimental Approach Contractility, c GMP levels, Ca2+ transient amplitudes and protein phosphorylation were measured in left ventricular muscle strips or ventricular cardiomyocytes from failing hearts of Wistar rats 6 weeks after myocardial infarction. Key Results CNP increased c GMP levels, evoked a NIR and LR in muscle strips, and caused phospholamban ( PLB) Ser16 and troponin I ( TnI) Ser23/24 phosphorylation in cardiomyocytes. Both the NIR and LR induced by CNP were reduced in the presence of a PKG blocker/c GMP analogue ( Rp-8- Br- Pet-c GMPS) and the SERCA inhibitor thapsigargin. CNP increased the amplitude of the Ca2+ transient and increased SERCA2 activity in cardiomyocytes. The CNP-elicited NIR and LR were not affected by the L-type Ca2+ channel activator BAY- K8644, but were abolished in the presence of isoprenaline (induces maximal activation of c AMP pathway). This suggests that phosphorylation of PLB and TnI by CNP causes both a NIR and LR. The NIR to CNP in mouse heart was abolished 8 weeks after cardiomyocyte-specific inactivation of the SERCA2 gene. Conclusions and Implications We conclude that CNP-induced PLB and TnI phosphorylation by PKG in concert mediate both a predictable LR as well as the less expected NIR in failing hearts. [ABSTRACT FROM AUTHOR]