Ca(2+)-channel blockers modulate the expression of interleukin-6 and interleukin-8 genes in human vascular smooth muscle cells.
Ca(2+)-channel blockers at therapeutic concentrations were shown to modulate several processes underlying inflammation, such as growth factor-mediated activation of genes coding for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in human vascular smooth muscle cells (VSMC) (Block et al., 1991), and for interleukins in human mesangial cells (Roth et al., 1992). Two Ca(2+)-channel blockers, Manidipine (Roth et al., 1992) and Verapamil (Walz et al., 1990) have been shown to induce the expression of the gene coding for interleukin-6 (IL-6). Here we demonstrate that the four Ca(2+)-channel blockers, Amlodipine, Felodipine, Isradipine and Manidipine, at nanomolar concentrations, activate the transcription of the genes encoding IL-6 and IL-8 in primary human VSMC and fibroblasts. Ca(2+)-channel blocker-induced transcription is subsequently followed by secretion of the two ILs into the growth medium of the cells. In addition, we compared the action of the Ca(2+)-channel blockers with that of propranolol, a beta-adrenoceptor antagonist, or with furosemide, a diuretic, all of which are known to lower blood pressure. However, in contrast to the dihydropyridines, the two latter drugs failed to affect the expression of the two IL genes.
Rödler
S
S
Department of Internal Medicine, University of Vienna, Austria.
Roth
M
M
Nauck
M
M
Tamm
M
M
Block
L H
LH
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D017311:Amlodipine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D020746:Calcium Channels, L-Type; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology; D015736:Felodipine / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005665:Furosemide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D017275:Isradipine / Q000494:pharmacology; D008168:Lung / Q000166:cytology; D009124:Muscle Proteins / Q000037:antagonists & inhibitors; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009578:Nitrobenzenes; D010879:Piperazines; D011433:Propranolol / Q000494:pharmacology; D014158:Transcription, Genetic / Q000235:genetics
D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D004232:Diuretics; D015850:Interleukin-6; D016209:Interleukin-8; D009124:Muscle Proteins; D009578:Nitrobenzenes; D010879:Piperazines; D017311:Amlodipine; C054218:manidipine; D005665:Furosemide; D011433:Propranolol; D015736:Felodipine; D017275:Isradipine