Racemic propranolol attenuates cardiac hypertrophy secondary to abdominal aortic banding-induced pressure overload by a mechanism independent of its effect on cardiac work load. This was only observed, however, using doses of propranolol that were much higher than those needed to induce β-adrenoceptor blockade. Thus, the question remains as to whether the antihypertrophic effect of propranolol depends on its ability to antagonize cardiac β-adrenoceptor-mediated action (positive chronotropic effect, trophic effect) or on β-adrenoceptor-independent action.
In a rat model of chronic pressure overload induced by abdominal aortic banding, we evaluated the effects on left ventricular hypertrophy (LVH) of the propranolol isomers, l-propranolol and d-propranolol, which compared to l-isomer is approximately 50-fold less potent as a β-adrenoceptor antagonist, but is similarly potent as a membrane-stabilizer, as well as of timolol, a non-selective β-adrenergic antagonist devoid of membrane stabilizing activity, and disopyramide, which is a membrane stabilizer, but not a β-adrenoceptor blocker.
Compared to sham-operated rats, banded rats had 30% greater left ventricular to body weight (LVW/BW) ratio (P< 0.01). The increase in LVW/BW ratio was significantly attenuated by treatment with 40 and 80 (but not 10) mg/kg per day of l-propranolol. Left ventricular hypertrophy was also prevented by d-propranolol, 40 and 80 mg/kg per day, and disopyramide, 50 mg/kg per day, whereas timolol, 30 and 60 mg/kg per day, showed no antihypertrophic effect. In separate groups of banded rats in which the reduction in heart rate induced by propranolol (80 mg/kg per day) was prevented by chronic cardiac pacing at 375 b.p.m., hypertrophy was again prevented, indicating that the effects of l-propranolol on LVH are not related to a reduction in cardiac work load.
In the aortic banding-induced model of LVH: (i) the antihypertrophic effect of propranolol is independent of its β-adrenergic blocking activity; and Iii) since disopyramide and D-propranolol also proved to be able to antagonize banding-induced LVH, the hypothesis is proposed that membrane-stabilizing activity, among the ancillary properties of propranolol, most likely accounts for the antihypertrophic effect of this drug.