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 constrictio n, in which enhanced myocardial production of endothelin-l could play a cru cial role. In the absence of drug treatment, after 1 week, aortic banding p rovoked an increase in carotid pressure associated with left ventricular hy pertrophy (29%; P<0.01). These changes were accompanied by increased myocar dial expression of preproendothelin-l (2.5 times; P<0.05) and skeletal alph a-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 v entricular weight as well as preproendothelin-l and skeletal alpha-actin ge ne expression. Carvedilol at a lower dose (7.5 mg . kg(-1) . d(-1)) and lac idipine 1 mg . kg(-1) . d(-1) had only moderate and nonsignificant effects on carotid pressure but largely prevented left ventricular hypertrophy (P<0 .01) and preproendothelin-l overexpression (P<0.05). Labetalol (60 mg . kg( -1) . d(-1)) tended to exert similar effects but insignificantly. These res ults show that the antihypertrophic properties of carvedilol and lacidipine are partly independent of their antihypertensive effects and may be relate d to their ability to blunt myocardial preproendothelin-l overexpression. M oreover, carvedilol at a dose of 7.5 mg . kg(-1) . d(-1) did not prevent my ocardial overexpression of skeletal alpha-actin, which suggests that, in th is model, reexpression of a fetal gene can be activated by pressure overloa d independently of cardiac hypertrophy.