Objective: Mice with genetic disruption of the guanylyl cyclase-A (GC-A) receptor for atrial natriuretic peptide (ANP), have chronic arterial hypertension and marked cardiac hypertrophy. Intriguingly, despite pronounced remodeling, cardiac contractile functions and cardiomyocyte Ca²⁺-handling are preserved and even enhanced. The present study aimed to characterize the specific molecular mechanisms preventing cardiac failure.

Methods and results: Contractile function and expression as well as phosphorylation of regulatory proteins were evaluated in isolated perfused working hearts from wild-type and GC-A KO mice under baseline conditions and during β₁-adrenergic stimulation. Ca_i²⁺-transients were monitored in Indo-1 loaded isolated adult cardiomyocytes. Cardiac contractile, especially lusitropic responsiveness to β-adrenergic stimulation was significantly increased in GC-A KO mice. This was concomitant to enhanced expression and activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), increased dual-site phosphorylation of phospholamban (PLB) at Ser¹⁶ and Thr¹⁷, enhanced amplitude of Ca_i²⁺ transients, and accelerated Ca_i²⁺ decay. In contrast, the expression of cardiac ryanodine receptors and phosphorylation at Ser²⁸⁰⁹ and Ser²⁸¹⁵ was not altered. Pharmacological inhibition of CaMKII-but not of protein kinase A-mediated PLB phosphorylation totally abolished the increased effects of β-adrenergic stimulation on cardiac contractility and Ca_i²⁺-handling. Thus, acceleration of sarcoplasmic reticulum Ca²⁺-uptake and increased availability of Ca²⁺ for contraction, both secondary to increased CaMKII-mediated PLB phosphorylation, seem to mediate the augmented responsiveness of GC-A KO hearts to catecholamines.

Conclusion: Our observations show that increased CaMKII activity enhances the contractile relaxation response of hypertrophic GC-A KO hearts to β-adrenergic stimulation and emphasize the critical role of CaMKII-dependent pathways in β₁-adrenoreceptor modulation of myocardial Ca²⁺-homeostasis and contractility.