Carvedilol and lacidipine prevent cardiac hypertrophy and endothelin-1 gene overexpression after aortic banding.
Carvedilol and lacidipine have been shown to exert cardioprotective effects in rat models of chronic hypertension. We investigated their effects in an acute model of pressure overload produced by suprarenal aortic constriction, in which enhanced myocardial production of endothelin-1 could play a crucial role. In the absence of drug treatment, after 1 week, aortic banding provoked an increase in carotid pressure associated with left ventricular hypertrophy (29%; P<0.01). These changes were accompanied by increased myocardial expression of preproendothelin-1 (2.5 times; P<0.05) and skeletal alpha-actin (3.6 times; P<0.05), but the expression of cardiac alpha-actin was not modified. Oral administration of carvedilol at a dose of 30 mg. kg(-1). d(-1) to rats with aortic banding normalized carotid pressure and left ventricular weight as well as preproendothelin-1 and skeletal alpha-actin gene expression. Carvedilol at a lower dose (7.5 mg x kg(-1) x d(-1)) and lacidipine 1 mg x kg(-1) x d(-1) had only moderate and nonsignificant effects on carotid pressure but largely prevented left ventricular hypertrophy (P<0.01) and preproendothelin-1 overexpression (P<0.05). Labetalol (60 mg x kg(-1) x d(-1)) tended to exert similar effects but insignificantly. These results show that the antihypertrophic properties of carvedilol and lacidipine are partly independent of their antihypertensive effects and may be related to their ability to blunt myocardial preproendothelin-1 overexpression. Moreover, carvedilol at a dose of 7.5 mg x kg(-1) x d(-1) did not prevent myocardial overexpression of skeletal alpha-actin, which suggests that, in this model, reexpression of a fetal gene can be activated by pressure overload independently of cardiac hypertrophy.
Massart
P E
PE
Department of Cardiovascular Physiology, Université Catholique de Louvain, Brussels, Belgium.
Donckier
J
J
Kyselovic
J
J
Godfraind
T
T
Heyndrickx
G R
GR
Wibo
M
M
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001018:Aortic Diseases / Q000150:complications; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D002339:Carotid Arteries / Q000503:physiopathology; D000077261:Carvedilol; D003251:Constriction, Pathologic; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics*; D016232:Endothelins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D007741:Labetalol / Q000494:pharmacology; D008026:Ligation; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood
D000199:Actins; D000959:Antihypertensive Agents; D002227:Carbazoles; D004095:Dihydropyridines; D019332:Endothelin-1; D016232:Endothelins; D011412:Propanolamines; D011498:Protein Precursors; D012333:RNA, Messenger; D000077261:Carvedilol; C060285:lacidipine; D012083:Renin; D007741:Labetalol