Bovine aortic endothelial and smooth muscle cells (SMC) and human skin fibroblasts (HSF) were used to study the effect of verapamil on cellular interactions with human low density lipoprotein (LDL). Verapamil, 10 to 50 microM, increased 125I-LDL uptake and degradation by 70% to 200% in the various cells after 24 to 48 hours of incubation. The increase in the total amount of LDL endocytosed, labeled with 3H-cholesteryl linoleate (3H-CL), was comparable to that determined with 125I-LDL. In HSF and SMC, a delay in 125I-LDL degradation and hydrolysis of 3H-CL was seen in cells treated for 3 to 24 hours with verapamil. Pretreatment of HSF with 50 microM verapamil for 24 hours and incubation with 2 to 50 micrograms 125I-LDL protein/ml for 1 hour resulted in a 50% to 200% increase in heparin releasable and in a 40% to 130% increase in cellular 125I-LDL. Thus, the increase in 125I-LDL binding and uptake in verapamil-treated cells was apparently due to an increase in receptor number, rather than in receptor affinity. The effect of verapamil on LDL uptake and degradation was also seen in cells that were pretreated for 24 hours and incubated with 125I-LDL in the absence of verapamil. The effect of verapamil was not apparent in LDL receptor-negative cells. Cycloheximide blocked the verapamil effect. The Na+ channel blocker, tetrodotoxin x 10(-6) M, caused a 30% to 50% increase in the total amount of LDL endocytosed, but no delay in LDL degradation; amiloride 2 x 10(-3) M was not effective. If the presently described effect of verapamil also occurs in vivo, this might contribute to the reported beneficial effects of Ca++ channel blockers in experimental atherosclerosis by promoting transfer of LDL cholesteryl ester from the aortic interstitium to a catabolic compartment.