Histamine-induced calcium transients in vascular smooth muscle cells: effects of verapamil and diltiazem.

We investigated the effects of verapamil and diltiazem on histamine-induced Ca2+ transients in vascular smooth muscle. 1) With the use of quin2 microfluorometry, cytosolic Ca2+ concentrations were directly measured in cultured vascular smooth muscle cells of the rat aorta. In the presence of extracellular Ca2+, histamine induced an elevation of cytosolic Ca2+ concentrations of a peak and plateau type. The peak component is due to a release of Ca2+ from cellular store sites, and the plateau component depends on extracellular Ca2+. Verapamil and diltiazem inhibited the plateau component, and the 50% inhibitive concentration (IC50) of verapamil and diltiazem for 10 microM histamine was 0.09 and 0.18 microM, respectively. Only at high concentrations did verapamil (IC50 = 8.7 microM) and diltiazem (IC50 = 95.7 microM) inhibit the Ca2+ release from the cellular store sites, as induced by 10 microM histamine. 2) Histamine, verapamil, and diltiazem competed with [3H]mepyramine for binding to the porcine aortic membranes, the order of potency being verapamil (Ki = 7.1 microM) greater than histamine (Ki = 18 microM) greater than diltiazem (Ki = 114 microM). From these results, we conclude that verapamil and diltiazem strongly inhibit the histamine-mediated, extracellular Ca2+-dependent intracellular [Ca2+] increase. In addition, verapamil and diltiazem seem to inhibit the release of Ca2+ from intracellular store sites, only at high concentrations, and probably by competing with histamine for binding to the H1-receptor. The inhibitory effects of Ca2+ antagonists on the histamine-induced contraction or spasm of vascular smooth muscle may well relate to these mechanisms.