Ca(2+)-channel blockers modulate the expression of interleukin-6 and interleukin-8 genes in human vascular smooth muscle cells.

ABSTRACT

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.