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Local, cardiac actions of ANP inhibit angiotensin II mediated cardiac remodeling
Author(s) -
Kuhn Michaela,
Kilic Ana,
Voss Melanie,
Zetsche Bernd,
Bubikat Alexander
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a314
Subject(s) - angiotensin ii , renin–angiotensin system , medicine , cardiology , pharmacology , receptor , blood pressure
Atrial natriuretic peptide (ANP) via its guanylyl cyclase‐A (GC‐A) receptor counteracts the systemic, hypertensive actions of angiotensin II (ANG II). Cardiomyocyte‐restricted disruption of GC‐A in mice (CM GC‐A KO) induces blood pressure ‐independent cardiac hypertrophy and fibrosis, suggesting that local, cardiac actions of ANP inhibit cell growth ( J Clin Invest 2003; 111 :). In the present study we investigated whether ANP/GC‐A can counteract not only the endocrine, but also the cardiac hypertrophic actions of ANG II. Cardiac remodeling in response to exogenous ANG II (osmotic minipumps. 300 and 2500 ng/kg/min, 14 days)was significantly exacerbated in CM GC‐A KO mice. This was accompanied by activation of mitogen‐activated protein kinases (MAPK) and of the phosphatase calcineurin. Cardiac calcineurin activity in response to ANG II was more pronounced in CM GC‐A KO as compared to control mice, whereas MAPK activation was similar in both genotypes. Fluorimetric measurements of Ca 2+ i transients in isolated, electrically paced adult cardiomyocytes indicated that myocyte diastolic Ca 2+ i levels were not different between genotypes. Systolic Ca 2+ i levels however were increased in GC‐A – deficient cardiomyocytes as compared to controls (peak amplitude of Ca 2+ i transients: 0.17 ± 0.02 vs. 0.10 ± 0.003; p< 0.05). Even more, ANG II‐induced Ca 2+ i increases were significantly enhanced (0.25 ± 0.03 vs. 0.17 ± 0.02; p<0.05). These results suggest that local ANP/GC‐A signalling inhibits ANG II ‐ stimulated, Ca 2+ /calcineurin ‐ mediated excessive cardiac remodeling. Supported by the Deutsche Forschungsgemeinschaft (SFB 487).