Action of probucol in arteries from normal and hypercholesterolaemic rabbits

Abstract

1 The effect of probucol on the vascular reactivity of different arteries isolated from rabbits was studied as well as its effects on the development of atherosclerosis in a cholesterol-fed rabbit model. 2 Probucol 1O6-5 x 10-4 M produced a concentration-dependent inhibition of the contractile responses induced by KCl (80 mM), the sequence for the IC50 was: mesenteric artery (5th branch, 4.8+2.6 x 10-5 M) >aorta (8.2+2.3 x l0-M) >femoral artery (>5 x 0-4 M). The response to noradrenaline was: mesenteric artery (5th branch, 4.2+ 1.3 x 10-5 M) >aorta (3.2+ 3.0 x 10-4 M) >femoral (> 5 X 10-4 M). 3 In the aorta, probucol (10-_-10-4 M) shifted the concentration-response curves to Ca2+ downward and to the right. 4 Probucol at 5 x 10' M and 5 x 10-4 M showed a reduction in the 45Ca2+ uptake in resting, nonstimulated aortic rings as well as the uptake induced by both noradrenaline 10-6 M and KC1 80 mM. 5 In experiments in vivo, probucol did not affect lipid profiles; however, drug-treatment significantly decreased the cholesterol content of aortic tissue and the extent of intimal surface covered with atherosclerotic lesions. 6 The vascular reactivity was recovered in femoral arteries from rabbits on the atherogenic diet plus probucol. 7 It is concluded that the effect of probucol in vascular smooth muscle can be attributed to an inhibition of Ca2+ entry through both potential-and receptor-operated pathways. Moreover our findings suggest that the effects of probucol on movement of calcium in vascular smooth muscle may play an important role in the mechanism of antiatherogenic properties of this drug.

Effects of Probucol on Atherosclerosis of apoE-Deficient or LDL Receptor-Deficient Mice

“…The time-coursed progressions of atherosclerotic lesions in apoE-deficient and LDLR-deficient mice are histopathologically similar to those observed in humans and other species [15 ± 17]. It has been reported that probucol attenuates lesion development in Watanabe heritable hyperlipidemic (WHHL) rabbits [18 ± 21], cholesterol-fed rabbits [22], and non-human primates fed a high-fat, high-cholesterol diet [23], although the effectiveness of probucol was questioned in some experiments [24,25]. In contrast, more recent data using murine models showed a new aspect of probucol on the development of atherosclerosis.…”

On the mechanism of selective action of probucol on the inwardly rectifying potassium current in GH3 lactotrophs

“…A previous study showing that probucol suppressed KCl-and norepinephrine-induced Ca 2+ influx [Del Rio et al, 1996] in blood vessels is compatible with our results. In our study, probucol at a concentration of 10 µM was able to suppress the amplitude of I Ca,L in GH 3 cells without altering the I-V relationship of I Ca,L .…”

“…-antagonistic properties in smooth muscle [Sgaragli et al, 1993;Del Rio et al, 1996]. However, we were unable to find any effect of probucol on Ca 2+ -activated or voltage-dependent K + currents in GH 3 cells.…”

Vascular targets of redox signalling in diabetes mellitus

“…Although the exact mechanisms that link diabetes and ROS with MMP expression are not fully understood, additional studies are necessary to further define MMPs as potential therapeutic targets in diabetic blood vessel dysfunction. [170,171,172,173], we could describe changes in subcellular (perinuclear and subplasmalemmal) Ca 2+ distribution in smooth muscle cells from diabetic patients [174] (Fig. 3).…”