The effect of nifedipine on lipid and monocyte infiltration of the subendothelial space

Abstract

Calcium channel blockade has been shown to inhibit experimental atherosclerosis in cholesterol-fed animals, and early clinical trials suggest its benefit in human subjects as well. Methods: To determine the effect of the calcium channel blocker nifedipine on lipid and monocyte infiltration of the subendothelial space, an endothelial cell (EC)-smooth muscle cell (SMC) brayer model of the arterial wall was incubated for 18 hours with nifedipine (0.1 ~g/ml). Iodine 125-labeled low-density lipoprotein (12SI-LDL) (10 ~g protein/ml) was then added to the upper-well medium. Results: After a 3-hour incubation period, nifedipine-treated bilayers showed an increased permeability to LDL (p < 10-7). Nffedipine had no effect on the membrane binding or cellular uptake of LDL by the EC but did increase SMC binding and uptake (p < 0.0005). U937 monocytes were found to incorporate 12sI-LDL in a concentration-dependent fashion, without saturation to 25 lzg/ml, the highest concentration studied. Nffedipine increased monocyte uptake of LDL (10 izg/ml; p < 0.003 but reduced monocyte movement through the EC barrier (p < 10-7). A study of the selective preincubation of each cell type (EC, SMC, and monocyte) with nifedipine indicated that this reduction was likely the result of a direct effect on the monocyte. Conclusions: Given the potential cytotoxic effects of the monocyte within the subendothelial space, nifedipine-induced inhibition of monocyte infiltration and enhancement of lipoprotein uptake by the SMC may be protective. (J VASC SURG 1993;17:841-8.) The observation that calcium and cholesterol content of the human aorta increases with age and calcium accumulation within the arterial intima precedes the development of atherosclerotic plaque led Blumethal et al. 1 postulate a putative role of calcium in atherosclerosis. Rosenblum et al.2 supported this hypothesis by demonstrating a direct correlation between elevated serum calcium levels and accelerated atherosclerosis in cholesterol-fed rabbits. Subsequently, the direct measurement of transcellular calcium flux allowed Strickberger et al. s to document an association between increased cyto-From the

Nifedipine-Induced Vascular Endothelial Growth Factor Secretion from Coronary Smooth Muscle Cells Promotes Endothelial Tube Formation via the Kinase Insert Domain-Containing Receptor/Fetal Liver Kinase-1/NO Pathway

“…CCB are believed to increase coronary blood flow by inhibiting the entry of Ca 2+ into smooth muscle cells (SMCs) through specific L-type calcium channel-blocking effects (4,5). However, CCB may also influence endothelial cells (ECs), which have not been shown to possess L-type calcium channels (6,7). In addition, Orth et al demonstrated that CCBs inhibited the proliferation of mesangial cells, which also lack L-type calcium channels (8).…”

Effects of efonidipine on platelet and monocyte activation markers in hypertensive patients with and without type 2 diabetes mellitus

“…Calcium channel blockers are widely used to treat hypertension and angina pectoris, because they provide effective coronary vasodilation, 2 and several studies have suggested an additional role for these drugs as anti-atherogenic agents, because they have been found to prevent the development of de novo angiographic lesions in human coronary arteries. 3,4 Moreover, a variety of antiatherogenic mechanisms of calcium channel blockers have been assessed, including effects on platelet aggregation, 5 leukocyte-endothelial cell adhesion, 6 monocyte infiltration of the subendothelium, 7 permeability of the endothelium 8 and/or media, 9 and smooth muscle cell migration 10 and proliferation. 11 Expression of cell adhesion molecules is increased in both insulin-dependent and non-insulin-dependent diabetes mellitus, 12 and these molecules have been implicated in the microvascular complications of diabetes.…”

Calcium Antagonists Ameliorate Ischemia-Induced Endothelial Cell Permeability by Inhibiting Protein Kinase C

“…4 However, calcium antagonists may also influence endothelial cells, which have not been shown to possess L-type calcium channels. 5 Direct effects on endothelial cells could be important, because the endothelium plays a major role in ischemiainduced tissue injury. Adhesion molecule expression, NO release, and the maintenance of endothelial cell-layer permeability are disturbed with ischemia.…”