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1 Department of Physiology and Biophysics, Cardiovascular Research Group, University of Calgary, Calgary, Alberta, Canada
* To whom correspondence should be addressed. E-mail: shimoni{at}ucalgary.ca.
Gender differences were studied in ventricular myocytes from insulin-deficient (type 1) diabetic rats. Cells were obtained by enzymatic dispersion of hearts from control male and female rats, and from rats made diabetic with streptozotocin (STZ, 100 mg/Kg), 7-14 days before experiments. Angiotensin II (ATII) content, measured by ELISA, was augmented in diabetic males but unaltered in diabetic females. In diabetic ovariectomized (ovx) females, ATII levels were augmented as in males. ATII affects multiple cellular pathways, including an activation of protein kinase C (PKC) and several tyrosine kinases, as well as the inhibition of protein kinase A (PKA). The involvement of these pathways in modulating outward K+ currents was studied. Transient and sustained outward K+ currents were measured using the whole cell voltage clamp method. In males, these currents are attenuated in diabetic conditions, but are augmented by the ATII-converting enzyme (ACE) inhibitor quinapril. Activation of protein kinase A (PKA) by 8-bromocAMP enhanced both K+ currents in cells from diabetic males. The augmentation of these currents by quinapril was blocked if PKA inhibition was maintained with RpCAMPS. The inhibition of tyrosine kinases by genistein also augmented K+ currents in cells from diabetic males. Action potentials were abbreviated by 8-bromo-cAMP and genistein. However, both genistein and 8-bromo-cAMP had no effect on K+ currents in cells from diabetic females. In cells from ovx-diabetic females, 8-bromo-cAMP and genistein enhanced these K+ currents, as in males. Inhibition of protein kinase C (PKC) augmented the transient and sustained K+ currents in cells from diabetic males and females. A contribution of non- ATII-dependent activation of PKC is suggested. These results describe some of the mechanisms that may underlie gender-specific differences in the development of cardiac disease and arrhythmias.
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