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

• Published in: Cardiovascular research 2009-04, Vol.82 (1), p.100-106
• Main Authors: Schmechel, Ariane, Grimm, Michael, El-Armouche, Ali, Höppner, Grit, Schwoerer, Alexander P., Ehmke, Heimo, Eschenhagen, Thomas
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Agonists - administration & dosage; Adrenergic beta-Agonists - toxicity; Animals; Atorvastatin; Atorvastatin Calcium; Atrial Natriuretic Factor - genetics; Atrial Natriuretic Factor - metabolism; Biological and medical sciences; Cardiology. Vascular system; Cardiomegaly - chemically induced; Cardiomegaly - prevention & control; Cell Membrane - drug effects; Cell Membrane - metabolism; Circadian Rhythm; Cytosol - metabolism; Desensitization; G-proteins; GTP-Binding Protein alpha Subunits, Gs - metabolism; GTP-Binding Protein gamma Subunits - metabolism; Heart; Heart - drug effects; Heart - physiopathology; Heart Rate - drug effects; Heptanoic Acids - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Infusion Pumps, Implantable; Isoprenaline; Isoproterenol - administration & dosage; Isoproterenol - toxicity; Male; Medical sciences; Myocardial Contraction - drug effects; Myocardium - metabolism; Protein Transport; Pyrroles - pharmacology; Rats; Rats, Wistar; RNA, Messenger - metabolism; β-adrenergic signalling
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvp005

Aims Atorvastatin blunts the response of cardiomyocytes to catecholamines by reducing isoprenylation of Gγ 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 × 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 × 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), Gγ and Gαs were partially translocated from the membrane to the cytosol. Conclusion In the rat heart, treatment with atorvastatin results in translocation of cardiac membrane Gγ and Gαs to the cytosol. This mechanism might contribute to protecting the heart from harm induced by chronic isoprenaline infusion without affecting heart rate.