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Increased effects of C‐type natriuretic peptide on contractility and calcium regulation in murine hearts overexpressing cyclic GMP‐dependent protein kinase I
Author(s) -
Wollert Kai C,
Yurukova Sevdalina,
Kilic Ana,
Begrow Frank,
Fiedler Beate,
Gambaryan Stepan,
Walter Ulrich,
Lohmann Suzanne M,
Kuhn Michaela
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705567
Subject(s) - phospholamban , contractility , medicine , endocrinology , protein kinase a , atrial natriuretic peptide , phosphodiesterase 3 , natriuretic peptide , phosphorylation , chemistry , cgmp dependent protein kinase , myocyte , calcium , biology , heart failure , biochemistry , mitogen activated protein kinase kinase
C‐type natriuretic peptide (CNP) and its receptor guanylyl cyclase (GC‐B) are expressed in the heart and modulate cardiac contractility in a cGMP‐dependent manner. Since the distal cellular signalling pathways remain unclear, we evaluated the peptide effects on cardiac function and calcium regulation in wild‐type (WT) and transgenic mice with cardiac overexpression of cGMP‐dependent protein kinase I (PKG I TG ). In isolated, perfused working WT hearts, CNP (10 n M ) provoked an immediate increase in the maximal rates of contraction and relaxation, a small increase in the left ventricular systolic pressure and a decrease in the time of relaxation. These changes in cardiac function were accompanied by a marked increase in the levels of Ser 16 ‐phosphorylated phospholamban (PLB). In PKG I TG hearts, the effects of CNP on cardiac contractility and relaxation as well as on PLB phosphorylation were markedly enhanced. CNP increased cell shortening and systolic Ca i 2+ levels, and accelerated Ca i 2+ decay in isolated, Indo‐1/AM‐loaded WT cardiomyocytes, and these effects were enhanced in PKG I‐overexpressing cardiomyocytes. 8‐pCPT‐cGMP, a membrane‐permeable PKG activator, mimicked the contractile and molecular actions of CNP, the effects again being more pronounced in PKG I TG hearts. In contrast, the cardiac reponses to β ‐adrenergic stimulation were not different between genotypes. Taken together, our data indicate that PKG I is a downstream target activated by the CNP/GC‐B/cGMP‐signalling pathway in cardiac myocytes. cGMP/PKG I‐stimulated phosphorylation of PLB and subsequent activation of the sarcoplasmic reticulum Ca 2+ pump appear to mediate the positive inotropic and lusitropic responses to CNP.British Journal of Pharmacology (2003) 140 , 1227–1236. doi: 10.1038/sj.bjp.0705567