Dexamethasone and cardiac potassium currents in the diabetic rat.
Experiments were designed to compare effects of dexamethasone on transient (Ipeak) and sustained (Isus) 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 Isus (by 28-31%). Ipeak was unchanged. Isus 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 Isus by dexamethasone. In marked contrast, dexamethasone had a significantly (P<0.015) smaller effect on Isus (11% increase) in cells from male STZ-diabetic rats, as compared to control cells. However, Isus augmentation in cells from female STZ-diabetic rats was normal (31% increase). In ovariectomized-diabetic rats, Isus 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.
Shimoni
Yakhin
Y
Cardiovascular Research Group, Department of Physiology and Biophysics, Health Sciences Centre, University of Calgary, 3330 Hospital Dr. N.W., Calgary, Alberta, Canada T2N 4N1. shimoni@ucalgary.ca
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005260:Female; D019833:Genistein / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D032342:Muscle Cells / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D015221:Potassium Channels; D011500:Protein Synthesis Inhibitors; D015638:Cytochalasin D; D003907:Dexamethasone; D003513:Cycloheximide; D019833:Genistein