Increased effects of C-type natriuretic peptide on cardiac ventricular contractility and relaxation in guanylyl cyclase A-deficient mice.
OBJECTIVE
The natriuretic peptides (NPs), atrial (ANP), B-type (BNP), and C-type (CNP) natriuretic peptides as well as their respective receptor-guanylyl cyclases (GC-A for ANP and BNP, and GC-B for CNP) are expressed in the heart. However, the local role of NPs in the regulation of cardiac contractility and the mutual interactions of NPs remain controversial. In the present study we evaluated the effects of ANP and CNP on cardiac function of wild-type (GC-A +/+) and GC-A-deficient (GC-A -/-) mice.


METHODS
The effects of NPs and their molecular mechanisms were assessed in the isolated perfused mouse working heart preparation.


RESULTS
In GC-A +/+ hearts, CNP exerted a biphasic action: an immediate increase in inotropy and lusitropy, followed by a slowly developing negative inotropic effect. These effects were mimicked by the cGMP-analogue, 8-pCPT-cGMP. In contrast, ANP did not affect cardiac function. In GC-A -/- hearts, the immediate contractile responses to CNP and 8-pCPT-cGMP were significantly enhanced. CNP increased cardiac cGMP levels and stimulated phospholamban (PLB) phosphorylation; the effect on PLB, but not cGMP, was enhanced in GC-A -/- hearts. In addition, cardiac expression of cGMP-dependent protein kinase (cGK I) was significantly increased in GC-A -/- mice.


CONCLUSIONS
CNP exerts a biphasic, initially positive inotropic and lusitropic, then negative inotropic effect in isolated working mouse hearts. A putative mechanism contributing to the immediate contractile responses is cGMP/cGK I-dependent phosphorylation of PLB and subsequent activation of the sarcoplasmic reticulum Ca(2+)-pump. ANP has no direct effects on cardiac contractility but chronic absence of its receptor, GC-A, results in increased responsiveness to CNP.
Pierkes
Melanie
M
Institute of Pharmacology and Toxicology, University of Münster, Domagkstrasse 12, D-48129 Münster, Germany.
Gambaryan
Stepan
S
Bokník
Peter
P
Lohmann
Suzanne M
SM
Schmitz
Wilhelm
W
Potthast
Regine
R
Holtwick
Rita
R
Kuhn
Michaela
M
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D006162:Guanylate Cyclase / Q000172:deficiency / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010766:Phosphorylation; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013873:Thionucleotides / Q000494:pharmacology; D000099211:Phospholamban
D009320:Atrial Natriuretic Factor; D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D000242:Cyclic AMP; D006152:Cyclic GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D020098:Natriuretic Peptide, C-Type; D017461:Receptors, Atrial Natriuretic Factor; D013873:Thionucleotides; D000099211:Phospholamban; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; C091715:atrial natriuretic factor receptor A