Objective: Calcineurin, a Ca²⁺ regulated protein phosphatase, links myocardial Ca²⁺ signaling with hypertrophic gene transcription. Calcineurin abundance increases in pressure-overload hypertrophy and may reduce agonist mediated phospholamban (PLB) phosphorylation to underlie blunted beta-adrenergic receptor (-AR) responsiveness in hypertension. This hypothesis was tested by measuring the effects of calcineurin inhibition on changes in cardiac contractility caused by beta-adrenergic stimulation in spontaneously hypertensive rats (SHR). Methods and Results: Female SHR (age: 7 months) and age matched female Wistar Kyoto (WKY) rats were studied. Heart weight to body weight ratio (P<0.01) and systolic blood pressure (P<0.01) were greater in SHR compared to WKY and were associated with increased myocardial calcineurin mRNA (CnA ) and activity (P<0.05). -AR stimulation with isoproterenol (ISO) increased calcineurin activity (P<0.05) in both WKY and SHR hearts and this activity was suppressed with cyclosporine A (CsA) treatment. In SHR, CsA improved left ventricular whole heart and isolated myocyte -AR responsiveness by normalizing PLB phosphorylation at Ser¹⁶ and Thr¹⁷ (P<0.05). These CsA-induced, PLB-mediated effects were associated with an augmentation in cardiomyocyte peak Ca²⁺ and a reduced rate (tau) and magnitude of diastolic Ca²⁺ during -AR stimulation. Conclusion: CsA normalized the blunted -AR responsiveness associated with hypertension, in part, by mitigating calcineurin activity while improving PLB phosphorylation and subsequent SR Ca²⁺ regulation.