High glucose concentration causes a rise in [Ca2+]i of cardiac myocytes

Abstract

Diabetes mellitus is associated with an elevation in the basal levels of cytosolic calcium ([Ca2+]i) of cardiac myocytes. This may be due in part to a glucose-induced elevation in [Ca2+]i. The present study examined this issue and explored the cellular pathways responsible for such a phenomenon. A total of 30 mM glucose, mannitol or choline chloride, but not urea, induced a time- and dose-dependent rise in the [Ca2+]i of cardiac myocytes. G protein inhibition by GDP beta S or pertussis toxin produced significant inhibition (> or = 80%) in the rise in [Ca2+]i. Incubation of cardiac myocytes in a calcium free medium or in media containing verapamil, nifedipine or amlodipine almost completely abolished the rise in [CA2+], while ryanodine produced only small reduction (10%) in the glucose-induced rise in [Ca2+]i. Rp-cAMP or H-89, inhibitors of the cAMP-protein kinase A pathway, produced a modest decrease in the rise in [Ca2+]i, while staurosporine (an inhibitor of PKC) and HOE 694 (an inhibitor of the Na(+)-H+ exchanger) had no effect on the rise in [Ca2+]i. The results indicate that the osmotic activity of glucose (cell shrinkage) activates G protein(s), most likely through a stretch receptor, which in turn stimulates calcium channels inhibitable by verapamil, nifedipine and amlodipine, thus permitting a calcium influx into the cardiac myocytes. The increased calcium entry may stimulate a calcium release from intracellular stores by a calcium-induced calcium release process. Thus, in cardiac myocytes direct activation of calcium channels, and to a small extent activation of the cAMP-protein kinase A, and calcium-induced calcium release mediate the high glucose-induced acute rise in their [Ca2+]i.