Attenuation of aortic banding-induced cardiac hypertrophy by propranolol is independent of beta-adrenoceptor blockade.
OBJECTIVE
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 beta-adrenoceptor blockade. Thus, the question remains as to whether the antihypertrophic effect of propranolol depends on its ability to antagonize cardiac beta-adrenoceptor-mediated action (positive chronotropic effect, trophic effect) or on beta-adrenoceptor-independent action.


METHODS
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 beta-adrenoceptor antagonist, but is similarly potent as a membrane-stabilizer, as well as of timolol, a non-selective beta-adrenergic antagonist devoid of membrane stabilizing activity, and disopyramide, which is a membrane stabilizer, but not a beta-adrenoceptor blocker.


RESULTS
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.


CONCLUSIONS
In the aortic banding-induced model of LVH: (i) the antihypertrophic effect of propranolol is independent of its beta-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.
Marano
Giuseppe
G
Laboratorio di Farmacologia, Istituto Superiore di Sanità, Rome, Italy. gmarano@iss.it
Palazzesi
Sergio
S
Fadda
Antonello
A
Vergari
Alessandro
A
Ferrari
Alberto U
AU
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001012:Aorta, Abdominal; D004206:Disopyramide / Q000494:pharmacology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D011433:Propranolol / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D013237:Stereoisomerism; D013999:Timolol / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D013999:Timolol; D011433:Propranolol; D004206:Disopyramide