Effect of diltiazem and verapamil on endothelin release by cultured human coronary smooth-muscle cells and endothelial cells

Recent data suggest that endothelin (ET) production is enhanced in coronary atherosclerotic lesions. In several studies, an anti-atherosclerotic effect has been attributed to calcium-channel antagonists. This study aimed to investigate whether ET release from cultured human coronary artery smooth muscle and endothelial cells is influenced by the calcium-channel antagonists diltiazem and verapamil. Coronary plaque smooth-muscle cells (SMCs) were isolated from primary stenosis plaque material. Normal coronary smooth muscle and endothelial cells were obtained from organ donors. Addition of diltiazem (5, 15 25, 50, or 100 mug/ml) and verapamil (0.25, 2.5, 25, 50, or 75 mug/ml) to the culture medium induced in all three cell types a dose-dependent reduction in ET secretion (coronary plaque SMCs: diltiazem 98.1 +/- 1.5, 94.9 +/- 5.0, 82.0 +/- 6.4**, 63.3 +/- 3.7***, 38.9 +/- 2.4*** control 108.4 +/- 2.8, verapamil 97.0 +/- 7.7, 91.9 +/- 5.5, 67.3 +/- 4.5**, 30.6 +/- 3.0***, 27.6 +/- 2.2***; control 103.4 +/- 6.1 pg/10(4) cells, n = 6; normal coronary SMCs: diltiazem 9.6 +/- 0.7, 8.7 +/- 0.6, 5.4 +/- 0.5***; 3.7 +/- 0.5***, 3.2 +/- 0.4***; control 10.7 +/- 0.5; verapamil 10.3 +/- 0.9, 10.0 +/- 0.7, 6.6 +/- 0.5***, 4.0 +/- 0.3***, 3.0 +/- 0.3***; control 11.1 +/- 0.6 pg/10(4) cells, n = 6; means +/- SEM, **p < 0.01, ***p < 0.001 vs. control). These data suggest that ET release from cultured coronary smooth muscle and endothelial cells is decreased by diltiazem and verapamil. In further studies, it remains to be elucidated whether the local application of diltiazem or verapamil might have a beneficial effect on the progression of coronary atherosclerosis.