Plant alkaloids, tetrandrine and hernandezine, inhibit calcium-depletion stimulated calcium entry in human and bovine endothelial cells

Abstract

Depletion of internal Ca*+ stores causes capacitative Ca*’ entry which occurs through non-selective cation channels sensitive to blockade by SK&F 96365. Recently, alkaloids of Chinese herbal medicinal origin, tetrandrine and hemandezine, have been shown to possess actions including inhibition of Ca2+ channels in non-excitable cell types. In this study, we compared the actions of these novel inhibitors to those of SK&F 96365 in fura-Zloaded endothelial cells from human umbilical vein and bovine pulmonary artery. Depletion of Ca*+ from the internal stores was accomplished in Ca*+-free medium using an endoplasmic reticulum Ca*+ pump inhibitor, cyclopiazonic acid (CPA) or receptor agonists, histamine and bradykinin. Stimulation with histamine or bradykinin caused a marked and rapid transient increase in Ca*+ signal whereas CPA caused a smaller amplitude increase of longer duration. Restoring Ca*’ to the medium caused marked and sustained increases in the fluorescence indicating movement of Ca*’ into the cytosol presumably stimulated by the emptied Ca*’ stores. SK&F 96365 as well as tetrandrine and hemandezine antagonized depletion-induced Ca*’ entry. The results suggest that these putative inhibitors interact with Ca*+ entry triggered by depletion of the internal Ca*+ stores and their action is presumed to be on the non-selective cation channels. Their effectiveness may be enhanced by the mechanisms which lead to the opening of the Ca*+ influx channel.