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Cardiovascular Research Advance Access first published online on January 9, 2009
This version [Corrected Proof] published online on February 4, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp005
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Treatment with atorvastatin partially protects the rat heart from harmful catecholamine effects

Ariane Schmechel1, Michael Grimm1, Ali El-Armouche1, Grit Höppner1, Alexander P. Schwoerer2, Heimo Ehmke2 and Thomas Eschenhagen1,*

1 Department of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
2 Department of Vegetative Physiology and Pathophysiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

* Corresponding author. Tel: +49 40 74105 2180; fax: +49 40 74105 4876. E-mail address: t.eschenhagen{at}uke.uni-hamburg.de

Aims: Atorvastatin blunts the response of cardiomyocytes to catecholamines by reducing isoprenylation of G{gamma} subunits. We examined whether atorvastatin exerts similar effects in vivo and protects the rat heart from harmful effects of catecholamines.

Methods and results: Rats were treated with atorvastatin (1 or 10 mg/kg x day) or H2O for 14 days per gavage. All three animal groups were subjected to restraint stress on day 10 and to infusions of isoprenaline (ISO; 1 mg/kg x day) or NaCl via minipumps for the last 4 days. Heart rate was measured by telemetry, left ventricular atrial natriuretic peptide (ANP) transcript levels by RT–PCR, and left atrial contractile function in organ baths. Heart rate was similar in all six study groups. In animals pre-treated with water, infusion of ISO induced an increase in heart-to-body weight ratio (HW/BW) by ~20%, an increase in ANP mRNA by ~350%, and a reduction in the inotropic effect of isoprenaline in left atrium by ~50%. In animals pre-treated with high-dose atorvastatin, the effects of ISO on HW/BW, ANP, and left atrial force were ~40, 50, and 40% smaller, respectively. Low dose atorvastatin had similar, albeit smaller effects. Atorvastatin treatment of NaCl-infused rats had only marginal effects. In cardiac homogenates from atorvastatin-treated rats (both NaCl- and ISO-infused), G{gamma} and G{alpha}s were partially translocated from the membrane to the cytosol.

Conclusion: In the rat heart, treatment with atorvastatin results in translocation of cardiac membrane G{gamma} and G{alpha}s to the cytosol. This mechanism might contribute to protecting the heart from harm induced by chronic isoprenaline infusion without affecting heart rate.

KEYWORDS Atorvastatin; Heart; β-adrenergic signalling; Isoprenaline; Desensitization; G-proteins

Time for primary review: 24 days


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