The atrial natriuretic peptide (ANP) - guanylyl cyclase A (GC-A) pathway has been implicated as an intrinsic moderator of cardiac hypertrophy. GC-A activation generates cGMP, which in turn activates cGMP-dependent protein kinase (PKG I) and counteracts Angiotensin II-induced increases in myocyte Ca²⁺_i-levels and cardiac hypertrophy. However, in hypertensive heart disease cardiac ANP levels are markedly increased and cGMP responses to ANP are blunted, indicating homologous desensitization of GC-A. Here we investigated how this process affects cardiomyocyte Ca²⁺-responses to ANP. Ventricular myocytes were isolated from mice subjected to transverse aortic constriction (TAC) or sham surgery (controls). Patch clamp recordings of L-type Ca²⁺ currents (I_Ca) were combined with fluorescent imaging of Ca²⁺_i-transients. In control myocytes ANP raised intracellular cGMP levels. This had no direct effect on basal I_Ca and Ca²⁺_i but fully prevented their stimulation by Angiotensin II. In hypertrophic myocytes from mice with TAC the cGMP-responses to ANP were diminished. Unexpectedly, ANP now itself enhanced I_Ca and Ca²⁺_i. Moreover, ANP did not inhibit the Ca²⁺-responses to Angiotensin II. Similar Ca²⁺-enhancing effects of ANP were observed in myocytes with genetic or pharmacological inhibition of PKG I. These "paradoxical" Ca²⁺-responses to ANP were abolished in the presence of TRPC inhibitors or in TRPC3/C6-deficient cardiomyocytes. Our study unravels a novel cGMP-independent signaling pathway of GC-A, which can provoke pathological Ca²⁺_i raises in cardiomyocytes. This pathway may be relevant in the heart under pathophysiological conditions and might increase the propensity to hypertrophy and arrhythmias when GC-A is desensitized by high ANP levels. Supported by SFB 487.