Amlodipine inhibits thapsigargin-sensitive CA(2+) stores in thrombin-stimulated vascular smooth muscle cells.
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.
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Département de Pharmacologie, Université René Descartes, 75015 Paris, France.
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D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D017275:Isradipine / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism* / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D017311:Amlodipine; D011189:Potassium Chloride; D019284:Thapsigargin; D014700:Verapamil; D013917:Thrombin; D000252:Calcium-Transporting ATPases; D004110:Diltiazem; D002118:Calcium; D017275:Isradipine