Gender-dependent attenuation of cardiac potassium currents in type 2 diabetic db/db mice.
Single ventricular myocytes were prepared from control db/+ and insulin-resistant diabetic db/db male mice at 6 and 12 weeks of age. Peak and sustained outward potassium currents were measured using whole-cell voltage clamp methods. At 6 weeks currents were fully developed in control and diabetic mice, with no differences in the density of either current. By 12 weeks both currents were significantly attenuated in the diabetic mice, but could be augmented by in vitro incubation with the angiotensin-converting enzyme (ACE) inhibitor quinapril (1 microM, 5-9 h). In cells from female db/db mice (12 weeks of age), K(+) currents were not attenuated and no effects of quinapril were observed. To investigate whether lack of insulin action accounts for these gender differences, cells were also isolated from cardiomyocyte-specific insulin receptor knockout (CIRKO) mice. Both K(+) currents were significantly attenuated in cells from male and female CIRKO mice, and action potentials were significantly prolonged. Incubation with quinapril did not augment K(+) currents. Our results demonstrate that type 2 diabetes is associated with gender-selective attenuation of K(+) currents in cardiomyocytes, which may underlie gender differences in the development of some cardiac arrhythmias. The mechanism for attenuation of K(+) currents in cells from male mice is due, at least in part, to an autocrine effect resulting from activation of a cardiac renin-angiotensin system. Insulin is not involved in these gender differences, since the absence of insulin action in CIRKO mice diminishes K(+) currents in cells from both males and females.
Shimoni
Yakhin
Y
Department of Physiology and Biophysics, Health Sciences Centre, 3330 Hospital Dr N.W., Calgary AB, Canada T2N 4N1. shimoni@ucalgary.ca
Chuang
Mariette
M
Abel
E Dale
ED
Severson
David L
DL
D000200:Action Potentials / Q000187:drug effects; D000375:Aging / Q000502:physiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002469:Cell Separation; D048429:Cell Size; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D000077583:Quinapril; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology; D012727:Sex Characteristics; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D016276:Ventricular Function
D000806:Angiotensin-Converting Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D044005:Tetrahydroisoquinolines; D011972:Receptor, Insulin; D000077583:Quinapril