High Glucose Increases [Ca²⁺]_i through an Increased Expression of T-Type Ca²⁺ Channels in Neonatal Rat Cardiomyocytes

Abstract 184 Cardiology: Signaling Mechanisms and Cardiovascular Function Platform, Sunday, 5/2

Hypertrophic cardiomyopathy as seen in infants of diabetic mothers can lead to hemodynamic compromise and death if not treated. It has been postulated that an elevation in cytosolic calcium ([Ca²⁺]_i) initiates the pathogenic in cardiomyocytes. This may be due in part to exposure of cells to high levels of glucose. Whole-cell patch-clamp analysis demonstrated an increase in the density of the T-type calcium current in primary culture neonatal cardiac myocytes treated with 25 mM glucose for 48-72 hours. Chronic glucose did not change the L-type calcium current density in these cells. The T-type Ca²⁺ current was blocked by nickel (50 mM) but not by nifedipine (10 mM). There was no difference in steady-state inactivation between glucose treated and untreated cells. Fluorescence measurements using fura-2 revealed an increase in [Ca²⁺]_i when depolarized with 50 mM KCl in the high glucose treated cells. This calcium influx was attenuated when nickel was co-perfused with 50 mM KCl. Quantitative RT-PCR studies demonstrated that mRNA levels of T-type calcium channels were elevated after 6 hours of glucose treatment. These results indicate that high glucose mediates a rise in [Ca²⁺]_i in neonatal cardiac myocytes through the expression of the T-type calcium channel gene. Therefore, T-type calcium channels may be an important therapeutic target for hypertrophic cardiomyopathy.