Insulin Inhibits Coronary Endothelial Cell Calcium Entry and Coronary Artery Relaxation

Abstract

Hyperinsulinemia is closely related to coronary artery disease. Endothelial cells are important for the control of vascular tone, and dysfunction of endothelial cells has been implicated in coronary artery disease. The direct effects of insulin on coronary endothelial cells are nonetheless unknown. In this study, the acute effects of high-dose insulin were investigated on agonist-induced intracellular Ca(2+) concentration ([Ca(2+)](i)) in porcine coronary endothelial cells and coronary relaxation. Bradykinin (10 n M ) and cyclopiazonic acid (100 microM), an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, provoked large increases in [Ca(2+)](i) in coronary endothelial cells. This increase was dose-dependently inhibited by a 10-min preincubation with high doses of insulin (10, 30, 100 mU/ml). Under Ca(2+)-free conditions, bradykinin and cyclopiazonic acid provoked transient, small increases in [Ca(2+)](i). These increases were not affected by pretreatment with insulin (100 mU/ml). Bradykinin (1, 10, 100, 1,000 n M ) and cyclopiazonic acid (10 microM) significantly relaxed porcine coronary artery rings precontracted with histamine (1 microM). The vasodilator effects of bradykinin and cyclopiazonic acid were dose-dependently inhibited by insulin. These acute effects were not observed at physiologic concentrations. Our data indicate that high-dose insulin inhibits agonist-induced Ca(2+) response in coronary endothelial cells and attenuates agonist-induced coronary vasodilatation. The study suggests that hyperinsulinemia might be associated with coronary artery disease via derangement of endothelial Ca(2+)-dependent functions.

Pregnancy-enhanced store-operated Ca2+ channel function in uterine artery endothelial cells is associated with enhanced agonist-specific transient receptor potential channel 3-inositol 1,4,5-trisphosphate receptor 2 interaction

“…More specifically, many ECs normally respond to agonist stimulation in a biphasic manner consisting of an initial transient peak rise in [Ca 2C ] i followed by a prolonged sustained phase, but in many cardiovascular disease states the sustained phase may be lost (Salameh & Dhein 1998, Kimura et al 2001, Kuroda et al 2001, Tran et al 2001. Furthermore, Steinert et al (2002) and Mahdy et al (1998) demonstrated that human fetal venous EC and maternal human hand vein EC show a loss of the sustained phase in subjects with preeclampsia, a condition that is characterized by hypertension (Mahdy et al 1998, Steinert et al 2002.…”

The Epoxy Group of Pramanicin Is Required for the Optimal Endothelium-Dependent Relaxation of Rat Aorta

“…It is possible that PMC exert inhibitory action on the Ca 2+ sequestration mechanisms in the ER, thus compromising their ability or capacity to buffer the entering Ca 2+ (9, 10). Indeed, cyclopiazonic acid (CPA), which is a modified ATA and also a potent inhibitor of sarcoplamic reticulum (SR) Ca 2+ -ATPase, also caused slow endothelium-dependent relaxation (7,11) via raising cytosolic Ca 2+ levels in cultured vascular endothelial cells (5,12,13). While CPA is a non-selective inhibitor for various SERCA isoforms (14, 15), PMC, being more selective for its action on endothelial cells, may be more selective for SERCA3, the major isoform present in endothelial cells.…”