Dexamethasone and cardiac potassium currents in the diabetic rat

Abstract

Experiments were designed to compare effects of dexamethasone on transient (i peak) and sustained (I sus) K + currents in control and diabetic rat myocytes. Ventricular myocytes were isolated from control or type 1 streptozotocin (STZ)-induced diabetic male and female rats. Currents were measured using whole-cell voltage-clamp methods. Incubation of cells from control males or females with 100 nM dexamethasone (5-9 h) significantly (P < 0.005) augmented I sus (by 28-31%). I peak was unchanged. I sus augmentation was abolished by cycloheximide or cytochalasin D, but not by inhibition of protein kinases A or C. Inhibition of tyrosine kinases by genistein (but not its inactive analog genistin) prevented the increase of I sus by dexamethasone. In marked contrast, dexamethasone had a significantly (P < 0.015) smaller effect on I sus (11% increase) in cells from male STZ-diabetic rats, as compared to control cells. However, I sus augmentation in cells from female STZ-diabetic rats was normal (31% increase). In ovariectomized-diabetic rats, I sus was unchanged by dexamethasone. The reduced effect in diabetic males might be due to preactivation of tyrosine kinases linking dexamethasone to current modulation. In conclusion, type I diabetes is associated with gender-specific changes in sensitivity of K + currents to glucocorticoids, linked to alterations in tyrosine-phosphorylated proteins. © 2005 Nature Publishing Group All rights reserved.