Gender differences in ANG II levels and action on multiple K+ current modulation pathways in diabetic rats.
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 (100 mg/kg) 7-14 days before experiments. ANG II content, measured by ELISA, was augmented in diabetic males but unaltered in diabetic females. In diabetic ovariectomized females, ANG II levels were augmented as in males. ANG II affects multiple cellular pathways including activation of protein kinase C (PKC) and several tyrosine kinases as well as 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 under diabetic conditions but are augmented by the ANG II-converting enzyme inhibitor quinapril. Activation of PKA by 8-bromo-cAMP enhanced both K(+) currents in cells from diabetic males. The augmentation of these currents by quinapril was blocked when PKA inhibition was maintained with the Rp isomer of 3',5'-cyclic monophosphorothioate. 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 ovariectomized diabetic females, 8-bromo-cAMP and genistein enhanced these K(+) currents as in males. Inhibition of PKC augmented the transient and sustained K(+) currents in cells from diabetic males and females. A contribution of non-ANG II-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.
Shimoni
Yakhin
Y
Cardiovascular Research Group, Department of Physiology and Biophysics, University of Calgary, Alberta, Canada T2N 4N1. shimoni@ucalgary.ca
Liu
Xiu-Fang
XF
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000097:blood*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019833:Genistein / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000077583:Quinapril; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D015398:Signal Transduction; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology
C105593:8-bromoadenosine-3',5'-cyclic monophosphorothioate; D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D015221:Potassium Channels; D044005:Tetrahydroisoquinolines; D013873:Thionucleotides; D000804:Angiotensin II; D015124:8-Bromo Cyclic Adenosine Monophosphate; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C088060:bisindolylmaleimide; D000077583:Quinapril