Amlodipine inhibits thapsigargin-sensitive CA2+ stores in thrombin-stimulated vascular smooth muscle cells

Département de Pharmacologie, Université René Descartes and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8604, Faculté de Médecine, 75015 Paris, France Ca 2+ channel blockers, such as amlodipine, inhibit vascular smooth muscle cell (VSMC) growth through interactions with targets other than L-type Ca 2+ channels. The effects of amlodipine on Ca 2+ movements in thrombin- and thapsigargin-stimulated VSMCs were therefore investigated by determining the variations of intracellular free Ca 2+ concentration in fura 2-loaded cultured VSMCs. Results indicated that 10-1,000 nM amlodipine inhibited 1 ) thrombin-induced Ca 2+ mobilization from a thapsigargin-sensitive pool and 2 ) thapsigargin-induced Ca 2+ responses, including Ca 2+ mobilization from internal stores and store-operated Ca 2+ entry. These effects of amlodipine do not involve L-type Ca 2+ channels and could not be reproduced with 100 nM isradipine, diltiazem, or verapamil. The inhibition by amlodipine of Ca 2+ mobilization appears therefore to be a specific property of the drug, in addition to its Ca 2+ channel-blocking property. It is suggested that amlodipine acts in this capacity by interacting with Ca 2+ -ATPases of the sarcoplasmic reticulum, thus modulating the enzyme activity. This mechanism might participate in the inhibitory effect of amlodipine on VSMC growth. calcium channel blockers; calcium mobilization; vascular smooth muscle cell growth