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Calcineurin inhibition normalizes -adrenergic responsiveness in the spontaneously hypertensive rat

¹Cardiovascular Research Center and the Departments of ²Kinesiology, ³Physical Therapy, and ⁴Physiology, Temple University, Philadelphia; and ⁵Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania

Submitted 13 June 2007 ; accepted in final form 6 September 2007

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 -adrenergic receptor (-AR) responsiveness in hypertension. This hypothesis was tested by measuring the effects of calcineurin inhibition on changes in cardiac contractility caused by -adrenergic stimulation in spontaneously hypertensive rats (SHR). Female SHR (age: 7 mo) and age-matched female Wistar-Kyoto rats (WKY) were studied. Heart weight-to-body weight ratio (P < 0.01) and systolic blood pressure (P < 0.01) were greater in SHR compared with 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 cyclosporin 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 (time constant of isovolumic pressure relaxation, tau) and magnitude of diastolic Ca²⁺ during -AR stimulation. In conclusion, CsA normalized the blunted -AR responsiveness associated with hypertension, in part, by mitigating calcineurin activity while improving PLB phosphorylation and subsequent sarcoplasmic reticulum Ca²⁺ regulation.

myocardium; hypertrophy; phosphatase; protein kinase A; calcium calmodulin kinase II

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