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Aims Phosphatase inhibitor-1 (I-1) is a conditional amplifier of β-adrenergic signalling downstream of protein kinase A by inhibiting type-1 phosphatases only in its PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus contributes to β-adrenergic desensitization. It is unclear whether this should be viewed as a predominantly adverse or protective response. Methods and results We generated transgenic mice with cardiac-specific I-1 overexpression (I-1-TG) and evaluated cardiac function and responses to catecholamines in mice with targeted disruption of the I-1 gene (I-1-KO). Both groups were compared with their wild-type (WT) littermates. I-1-TG developed cardiac hypertrophy and mild dysfunction which was accompanied by a substantial compensatory increase in PP1 abundance and activity, confounding cause–effect relationships. I-1-KO had normal heart structure with mildly reduced sensitivity, but unchanged maximal contractile responses to β-adrenergic stimulation, both in vitro and in vivo. Notably, I-1-KO were partially protected from lethal catecholamine-induced arrhythmias and from hypertrophy and dilation induced by a 7 day infusion with the β-adrenergic agonist isoprenaline. Moreover, I-1-KO exhibited a partially preserved acute β-adrenergic response after chronic isoprenaline, which was completely absent in similarly treated WT. At the molecular level, I-1-KO showed lower steady-state phosphorylation of the cardiac ryanodine receptor/Ca2 release channel and the sarcoplasmic reticulum (SR) Ca2+ATPase-regulating protein phospholamban. These alterations may lower the propensity for diastolic Ca2 release and Ca2 uptake and thus stabilize the SR and account for the protection. Conclusion Taken together, loss of I-1 attenuates detrimental effects of catecholamines on the heart, suggesting I-1 downregulation in heart failure as a beneficial desensitization mechanism and I-1 inhibition as a potential novel strategy for heart failure treatment. [ABSTRACT FROM AUTHOR]