The effects of antihypertensive agents on atherosclerosis-related parameters of human aorta intimal cells.

Four antihypertensive agents - amlodipine, verapamil, propranolol and perindoprilat - were studied in human cell cultures. Antiatherogenic activity was investigated using uninvolved human aortic smooth muscle intima cells and atherogenic serum obtained from patients with coronary atherosclerosis. Amlodipine and verapamil significantly inhibited serum-induced increases in cholesterol content, cell-proliferative activity and protein synthesis in the cultured cells. Propranolol increased all three parameters, while perindoprilat had no effects. In addition, amlodipine and verapamil significantly lowered the intracellular cholesterol content of smooth muscle cells derived from atherosclerotic plaque and inhibited cell proliferation and protein synthesis. Propranolol increased all of these parameters, while perindoprilat produced no effects. The antiatherogenic and antiatherosclerotic actions of verapamil and amlodipine were confirmed in an ex vivo model. These studies demonstrated a beneficial antiatherosclerotic effect of amlodipine that was greater than that of verapamil. Perindoprilat had a neutral effect on atherosclerotic parameters, while the action of propranolol appeared to be potentially detrimental.

Antiatherosclerotic and antiatherogenic effects of a calcium antagonist plus statin combination: amlodipine and lovastatin.

Recently, the Regression Growth Evaluation Statin Study (REGRESS) demonstrated the synergistic, antiatherogenic effect of lipid-lowering therapy with pravastatin in combination with calcium antagonists. This combination retarded the progression of stenosis and reduced the number of new lesions more effectively than did statin therapy alone. In the present study, our objective was to elucidate the mechanism of this more pronounced effect of the statin-calcium antagonist combination on the atherosclerotic lesion. Smooth muscle cells cultured from the subendothelial intima of the human aorta were incubated with whole blood serum or with low-density lipoprotein (LDL) taken from patients cotreated with lovastatin and amlodipine. Serum added to the cells cultured from the atherosclerotic lesion reduced cell cholesterol. Such an antiatherosclerotic effect of cotreatment with amlodipine-lovastatin was revealed in this study and was more pronounced than the effect of treatment with either amlodipine or lovastatin alone. LDL isolated from atherogenic plasma stimulated cell cholesterol accumulation. Treatment with amlodipine alone and the amlodipine-lovastatin combination ameliorated the atherogenic effect of LDL. As compared with amlodipine alone, the combination demonstrated a considerably higher antiatherogenic effect on LDL atherogenicity. Amlodipine-lovastatin cotreatment increased sialic acid and decreased the susceptibility of LDL to oxidation more effectively than amlodipine alone. In addition, combination therapy reduced the LDL negative charge, while amlodipine alone was impotent. These findings may serve as an explanation of the more pronounced antiatherogenic effect at the lipoprotein level of amlodipine-lovastatin combined therapy compared with amlodipine therapy alone.

Direct anti-atherosclerosis-related effects of garlic.

Direct anti-atherosclerosis-related effects of garlic were studied using cell culture. An aqueous extract from garlic powder (GPE) was added to smooth muscle cells cultured from atherosclerotic plaques of human aorta. During a 24-hour incubation, GPE significantly reduced the level of cholesteryl esters and free cholesterol in these cultured cells and inhibited their proliferative activity. In addition, GPE significantly reduced cholesterol accumulation and inhibited cell proliferation stimulated by blood serum taken from patients with angiographically assessed coronary atherosclerosis, i.e. GPE reduced atherogenic manifestations of patients' serum. Garlic effect on blood atherogenicity of patients with coronary atherosclerosis has also been studied ex vivo. Following a 24-hour incubation with cultured cells, patients' blood serum caused an increase of total cell cholesterol. Blood serum taken 2 hours after an oral administration of 300 mg garlic powder tablet caused substantially less cholesterol accumulation in cultured cells. This suggests that garlic powder manifests direct anti-atherogenic-related action not only in vitro but also in vivo.

Use of cell culture for optimisation of direct antiatherogenic therapy with verapamil.

The potential of verapamil to prevent atherogenesis induced by atherogenic serum in cell culture was investigated. Smooth muscle cells were cultured from human aortic intima and incubated with blood serum from patients with coronary artery disease. Only serum causing a significant rise in total cholesterol content in cultured cells during a 24-hour incubation period was used. The addition of verapamil to cells decreased serum-induced cholesterol accumulation. The maximum antiatherogenic effect of verapamil in vitro was recorded at 10(-5) to 10(-4) mol/L. Blood serum obtained from patients before and after oral verapamil administration was added to cultured cells. The atherogenic potential of serum obtained after verapamil administration was significantly lower than the predose value. To optimise direct antiatherogenic therapy with verapamil, the minimum dose that produced the maximum effect was established as 30 to 40mg. Using a 40mg dose, the maximum effect of oral verapamil was observed 3 hours after administration. A second 40mg dose was given 5 hours after the first dose, when the blood serum atherogenic potential was about 40% of the predose value and rising. This second dose maintained the atherogenic potential of serum at about 40%. Thus, to decrease atherogenic potential of serum and to maintain it at a low level, verapamil should be administered at a dose of 40mg 5 times daily with a 4- to 5-hour interval between doses.