Amlodipine inhibits thapsigargin-sensitive Ca2+ stores in thrombin-stimulated vascular smooth muscle cells

Abstract

Ca2+ channel blockers, such as amlodipine, inhibit vascular smooth muscle cell (VSMC) growth through interactions with targets other than L-type Ca2+ channels. The effects of amlodipine on Ca2+ movements in thrombin- and thapsigargin-stimulated VSMCs were therefore investigated by determining the variations of intracellular free Ca2+ concentration in fura 2-loaded cultured VSMCs. Results indicated that 10-1,000 nM amlodipine inhibited 1) thrombin-induced Ca2+ mobilization from a thapsigargin-sensitive pool and 2) thapsigargin-induced Ca2+ responses, including Ca2+ mobilization from internal stores and store-operated Ca2+ entry. These effects of amlodipine do not involve L-type Ca2+ channels and could not be reproduced with 100 nM isradipine, diltiazem, or verapamil. The inhibition by amlodipine of Ca2+ mobilization appears therefore to be a specific property of the drug, in addition to its Ca2+ channel-blocking property. It is suggested that amlodipine acts in this capacity by interacting with Ca2+-ATPases of the sarcoplasmic reticulum, thus modulating the enzyme activity. This mechanism might participate in the inhibitory effect of amlodipine on VSMC growth.