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Impaired cardiac β-adrenoceptor signaling is an important cause of sepsis-induced myocardial depression in man and experimental animals. We examined the effect of atorvastatin (ATR) pretreatment on myocardial β1-adrenoceptor (β1-AR) expressions and post-receptor signaling in a mouse model of sepsis (cecal ligation and puncture [CLP]). After 20 ± 2 h of surgery, hearts were isolated for the measurement of left ventricular functions (left ventricular developed pressure, dp/dt(max) and dp/dt(min)) using Langendorff setup. Western blot was used to determine β1-AR and G protein-coupled receptor kinase 2 protein expressions. Real-time polymerase chain reaction was done to determine β1-AR mRNA expression. Atorvastatin prevented sepsis-induced decrease in left ventricular functions, such as left ventricular developed pressure (CLP 75.90 ± 0.53 vs. ATR 100.24 ± 1.64 mmHg), dp/dtmax (CLP 3,742 ± 71 vs. ATR 4,291 ± 88 mmHg/s), and dp/dt(min) (CLP -1,010 ± 24 vs. ATR -1,346 ± 84 mmHg/s). Associated with functional impairments, sepsis decreased both myocardial β1-AR protein and mRNA expressions by 52% ± 9% and 62% ± 7%, respectively. However, ATR treatment of CLP mice (ATR) preserved β1-AR protein (96% ± 11%) and mRNA (88% ± 14%) expressions comparable to sham-operated level. Furthermore, it not only attenuated sepsis-induced decrease in basal cardiac adenosine 3',5'-cyclic monophosphate content (CLP 1.30 ± 0.27 vs. ATR 6.30 ± 0.67 pmol/mg protein), but also prevented its refractoriness to dobutamine stimulation (CLP 1.72 ± 0.27 vs. ATR 10.83 ± 1.37 pmol/mg protein). Atorvastatin also inhibited sepsis-induced increase in cardiac G protein-coupled receptor kinase 2 protein expression (CLP 1.73 ± 0.18-fold vs. ATR 1.10 ± 0.18-fold), protein kinase A activity (CLP 1.12 ± 0.14 vs. ATR 0.66 ± 0.08 U/mg protein) and plasma catecholamines (CLP 138 ± 22 vs. ATR 59 ± 2 pg/mL). In conclusion, ATR seems to improve left ventricular functions in vitro through the preservation of β(1)-AR signaling in sepsis.

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