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Probucol decreases and bezafibrate increases plasma high density lipoprotein-cholesterol (HDL-C) levels in humans. This study was performed to determine whether the HDL-C-lowering effects of probucol could be reversed by treatment with bezafibrate in hypercholesterolemic rabbits. Forty-nine normolipidemic Japanese White rabbits were divided into 5 groups [group 1: normal chow; group 2: 0.2% cholesterol (Ch) diet; group 3: 0.2% Ch and 1% probucol diet; group 4: 0.2% Ch and 1% bezafibrate diet; group 5: 0.2% Ch and 1% probucol plus 1% bezafibrate diet] and treated for 8 weeks. Plasma lipids, cholesteryl ester transfer protein (CETP) activity in the lipoprotein-deficient plasma fraction, CETP mRNA in liver tissue and plasma drug concentrations were investigated. Serum total cholesterol (TC) increased after the rabbits in groups 2, 3, 4 and 5 were fed Ch, but overall, no significant differences were observed in serum TC and triglyceride (TG) among these groups. Serum HDL-C levels increased (p

The combined effects of pravastatin and probucol on high- density lipoprotein (HDL) apolipoprotein (apo) A-I kinetics in cholesterol (Ch)-fed rabbits were investigated. Japanese White rabbits were treated with 0.15% pravastatin and 0.5% Ch (group 1) or 0.15% pravastatin plus 1% probucol and 0.5% Ch (group 2) for 2 months. After treatment, the serum total cholesterol levels in groups 1 and 2 had significantly (p < 0.01) increased (37.4 +/- 6.7 mg/dl vs 117.1 +/- 46.4 mg/dl, and 31.4 +/- 4.9 mg/dl vs 143.0 +/- 84.5 mg /dl, respectively). The serum HDL-cholesterol levels in both groups decreased (18.2 +/- 2.8 mg/dl, vs 16.2 +/- 3.7 mg/dl p < 0.01 for group 1; 18.2 +/- 1.9 mg/dl vs 15.5 +/- 4.5 mg/dl, ns for group 2). Apo A-I kinetics were assessed by injecting (125)I-labeled HDL intravenously into both groups of rabbits, and taking blood samples periodically for 6 days. Kinetic parameters calculated from apo A-I specific radioactivity decay curves showed that the apo A-I fractional catabolic rates in rabbits fed pravastatin and Ch (group 1) were significantly less than those in rabbits fed pravastatin plus probucol and Ch (group 2) (0.546 +/- 0.017 /day vs 0.730 +/- 0.126 /day, p < 0.05), while the synthetic rate of apo A-I was lower in group 2 than in group 1 (14.76 +/- 1.71 mg/kg per day vs 11.21 +/- 2.38 mg/kg per day, respectively, p < 0.01). These data indicate that pravastatin and probucol have different effects on HDL-apo A-I kinetics in a diet which includes cholesterol.

To clarify the relationship between the dilatation of angiographically non-stenotic coronary artery segments in response to isosorbide dinitrate (ISDN), and serum lipids, 5 coronary segments in 7 patients with familial hypercholesterolemia (FH) and 43 patients with non-familial hypercholesterolemia (non-FH), who had either 1- or 2-vessel coronary heart disease, were investigated. The serum total cholesterol level was significantly greater in FH than in non-FH. Before and after the direct intracoronary injection of ISDN, coronary diameter was measured by a computer-assisted coronary angiography analysis system. The order of the dilative responses in coronary segments in non-FH patients (segments: #5 > #11 > #6 > #13 > #7) was exactly the same as the order of their original diameters, while the ratio of the increase in diameter (after/before ISDN injection) did not differ among any of the segments (mean: 1.08-fold increase). In the non-FH group, no correlation was found between the serum total cholesterol, triglyceride, low-density lipoprotein-cholesterol, or high-density lipoprotein-cholesterol, and the ratio of the coronary diameter after and before injection of ISDN. Moreover, hypercholesterolemia in non-FH did not affect the coronary dilative response to ISDN injection. In the FH group, although the original diameter of each segment did not differ from that in the non-FH group, the ratio of the diameter after and before injection of ISDN was significantly smaller in FH than in non-FH (p < 0.01). These results suggest that a non-stenotic coronary artery in FH has a lower capacity for vasodilation in response to ISDN. Although hypercholesterolemia was excluded as a factor which may suppress the capacity for coronary dilation in non-FH, spontaneous hypercholesterolemia in FH may affect medial smooth muscle functions of the coronary artery.