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Local Actions of Atrial Natriuretic Peptide Counteract Angiotensin II Stimulated Cardiac Remodeling

Ana Kili¹, Alexander Bubikat¹, Birgit Gaßner, Hideo A. Baba and Michaela Kuhn

Institute of Physiology (A.K., A.B., B.G., M.K.), University of Würzburg, 97070 Würzburg, Germany; and Institute of Pathology (H.A.B.), University of Duisburg-Essen, 47057 Duisburg, Germany

Address all correspondence and requests for reprints to: Michaela Kuhn, Physiologisches Institut der Universität Würzburg, Röntgenring 9, D-97070 Würzburg, Germany. E-mail: michaela.kuhn{at}mail.uni-wuerzburg.de.

The cardiac hormones atrial and brain natriuretic peptides (NPs) counteract the systemic, hypertensive, and hypervolemic actions of angiotensin II (Ang II) via their guanylyl cyclase-A (GC-A) receptor. In the present study, we took advantage of genetically modified mice with conditional, cardiomyocyte (CM)-restricted disruption of GC-A (CM GC-A knockout mice) to study whether NPs can moderate not only the endocrine but also the cardiac actions of Ang II in vivo. Fluorometric measurements of [Ca²⁺]_i transients in isolated, electrically paced adult CMs showed that atrial NP inhibits the stimulatory effects of Ang II on free cytosolic Ca²⁺ transients via GC-A. Remarkably, GC-A-deficient CMs exhibited greatly enhanced [Ca²⁺]_i responses to Ang II, which was partly related to increased activation of the Na⁺/H⁺-exchanger NHE-1. Chronic administration of Ang II to control and CM GC-A knockout mice (300 ng/kg body weight per minute via osmotic minipumps during 2 wk) provoked significant cardiac hypertrophy, which was markedly exacerbated in the later genotype. This was concomitant to increased cardiac expression of NHE-1 and enhanced activation of the Ca²⁺/calmodulin-dependent prohypertrophic signal transducers Ca²⁺/calmodulin-dependent kinase II and calcineurin. On the basis of these results, we conclude that NPs exert direct local, GC-A-mediated myocardial effects to antagonize the [Ca²⁺]_i-dependent hypertrophic growth response to Ang II.