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


RESULTS
Rats were treated with atorvastatin (1 or 10 mg/kg x day) or H(2)O 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 approximately 20%, an increase in ANP mRNA by approximately 350%, and a reduction in the inotropic effect of isoprenaline in left atrium by approximately 50%. In animals pre-treated with high-dose atorvastatin, the effects of ISO on HW/BW, ANP, and left atrial force were approximately 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.


CONCLUSIONS
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.
Schmechel
Ariane
A
Department of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
Grimm
Michael
M
El-Armouche
Ali
A
Höppner
Grit
G
Schwoerer
Alexander P
AP
Ehmke
Heimo
H
Eschenhagen
Thomas
T
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000069059:Atorvastatin; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced / Q000517:prevention & control; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002940:Circadian Rhythm; D003600:Cytosol / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015918:Infusion Pumps, Implantable; D007545:Isoproterenol / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D021381:Protein Transport; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000318:Adrenergic beta-Agonists; D044388:GTP-Binding Protein gamma Subunits; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D000069059:Atorvastatin; D019205:GTP-Binding Protein alpha Subunits, Gs; D007545:Isoproterenol