Dual effects of the antioxidant agents probucol and carvedilol on proliferative and fatty lesions in hypercholesterolemic rabbits.
The in vivo direct antiatherogenic activity of the antioxidant probucol (200 mg/kg per day) or the beta-blocker with antioxidant properties carvedilol (10 and 20 mg/kg per day) was tested in the same animal in two different types of atherosclerotic lesion (proliferative and fatty lesions) induced in cholesterol-fed rabbits (1%). Drugs were given daily mixed with standard diet for 8 weeks; body weight and plasma lipid profile were not different among groups throughout the study. Aortic fatty lesions were induced by cholesterol feeding (n = 25 in each group) and their extent expressed as % of aorta inner surface covered by plaques was significantly reduced by both drugs (28.2+/-9.6%, P <0.05, 19.9+/-6.2%, P <0.01 for low- and high-dose carvedilol, respectively; 22.3+/-7.6%, P <0.01 for probucol, versus 41.6+/-10.7% in control rabbits). Proliferative lesions were obtained by positioning a hollow silastic collar around one carotid artery 6 weeks after dietary and drug treatments started (n = 5 in each group). The neointimal formation, mostly composed by myocytes, was determined by measuring cross-sectional thickness ratio of intimal (I) and medial (M) tissue of fixed arteries. In untreated animals, collared arteries resulted in a significant neointimal cell accumulation compared to the sham (1.10+/-0.14 versus 0.02+/-0.01) without change in medial thickness. I/M ratio was reduced by about 50% in animals treated with probucol (0.51+/-0.1) and carvedilol (0.66+/-0.21 and 0.52+/-0.1 in the low- and high-dose group, respectively). Total plasma TBARS were more than 50% lower in both probucol- and high-dose carvedilol-treated rabbits. Results show that pharmacological pretreatment with antioxidants directly inhibits early atherogenic processes, representing a potentially useful approach in the prevention of atherosclerosis.
Donetti
E
E
Institute of Pharmacological Sciences, University of Milan, Italy.
Soma
M R
MR
Barberi
L
L
Paoletti
R
R
Fumagalli
R
R
Roma
P
P
Catapano
A L
AL
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta / Q000473:pathology; D001158:Arteries / Q000473:pathology*; D001161:Arteriosclerosis / Q000150:complications / Q000473:pathology* / Q000517:prevention & control; D002227:Carbazoles / Q000494:pharmacology*; D002339:Carotid Arteries / Q000473:pathology; D000077261:Carvedilol; D002455:Cell Division; D006937:Hypercholesterolemia / Q000150:complications / Q000473:pathology*; D008297:Male; D011341:Probucol / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology*; D011817:Rabbits; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
D000319:Adrenergic beta-Antagonists; D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D000975:Antioxidants; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D011341:Probucol