title: Local actions of atrial natriuretic peptide counteract angiotensin II stimulated cardiac remodeling.
abstract: 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 [Ca(2+)](i) transients in isolated, electrically paced adult CMs showed that atrial NP inhibits the stimulatory effects of Ang II on free cytosolic Ca(2+) transients via GC-A. Remarkably, GC-A-deficient CMs exhibited greatly enhanced [Ca(2+)](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 Ca(2+)/calmodulin-dependent prohypertrophic signal transducers Ca(2+)/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 [Ca(2+)](i)-dependent hypertrophic growth response to Ang II.
authors.affiliation: Physiologisches Institut der Universität Würzburg, Röntgenring 9, D-97070 Würzburg, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Kilić
authors.forename: Alexander
authors.initials: A
authors.lastname: Bubikat
authors.forename: Birgit
authors.initials: B
authors.lastname: Gassner
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhn
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D020013:Calcium Signaling / Q000502:physiology; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor