Hypercholesterolaemia exacerbates ventricular remodelling after myocardial infarction in the rat: role of angiotensin II type 1 receptors.
OBJECTIVE
Diet-induced hypercholesterolaemia exacerbates post-myocardial infarction (MI) ventricular remodelling and heart failure, but the mechanism of this phenomenon remains unknown. This study examined whether worsening of post-MI ventricular remodelling induced by dietary hypercholesterolaemia was related to upregulation of angiotensin II type 1 (AT1) receptor in the rat heart.


METHODS
MI was induced surgically in rats fed normal or high cholesterol diet. Both groups of rats were then assigned to control, atorvastatin, losartan or atorvastatin+losartan-treated subgroups and followed for 8 weeks. Left ventricular (LV) function was assessed with echocardiography. In isolated hearts, LV pressures were measured with a latex balloon and a tip catheter. AT1-receptor density was assessed in LV membranes with radioligand-binding assays.


RESULTS
High cholesterol diet exacerbated LV dilation and dysfunction in post-MI hearts. Atorvastatin or losartan prevented these hypercholesterolaemia-induced effects, whereas their combination was not more effective than each drug alone. AT1 receptors were upregulated 8 weeks after MI, this was further increased by hypercholesterolaemia and restored to baseline levels by atorvastatin.


CONCLUSIONS
Hypercholesterolaemia exacerbated LV remodelling and dysfunction in post-MI rat hearts and upregulated cardiac AT1 receptors. All these effects were effectively prevented by atorvastatin. Thus, the pleiotropic statin effects may include interference with the renin-angiotensin system through downregulation of AT1 receptors.
Maczewski
M
M
Department of Clinical Physiology, Medical Center of Postgraduate Education, Warsaw, Poland. maczmich@cmkp.edu.pl
Maczewska
J
J
Duda
M
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D004359:Drug Therapy, Combination; D004452:Echocardiography; D006538:Heptanoic Acids / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000517:prevention & control; D020257:Ventricular Remodeling
D047228:Angiotensin II Type 1 Receptor Blockers; D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D044140:Receptor, Angiotensin, Type 1; D000069059:Atorvastatin; D019808:Losartan