Local actions of atrial natriuretic peptide counteract angiotensin II stimulated cardiac remodeling.
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.
Kilić
Ana
A
Physiologisches Institut der Universität Würzburg, Röntgenring 9, D-97070 Würzburg, Germany.
Bubikat
Alexander
A
Gassner
Birgit
B
Baba
Hideo A
HA
Kuhn
Michaela
M
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*
D012333:RNA, Messenger; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor