Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats.
The incidence of diabetes mellitus is increasing. Cardiac dysfunction often develops, resulting in diverse arrhythmias. These arise from ion channel remodeling or from altered speed and pattern of impulse propagation. Few studies have investigated impulse propagation in the diabetic heart. We previously showed a reduced conduction reserve in the diabetic heart, with associated changes in intercellular gap junctions. The present study investigated whether these effects are sex specific. Hearts from control and streptozotocin-diabetic male and female rats were used. Optical mapping was performed with the voltage-sensitive dye di-4-ANEPPS, using Langendorff-perfused hearts. Isolated ventricular cells and tissue sections were used for immunofluorescent labeling of the gap junction protein connexin43 (Cx43). The gap junction uncoupler heptanol (0.75 mM) or elevated K(+) (9 mM, to reduce cell excitability) produced significantly greater slowing of propagation in diabetic males than females. In ovariectomized diabetic females, 9 mM K(+) slowed conduction significantly more than in nonovariectomized females. The subcellular redistribution (lateralization) of the gap junction protein Cx43 was smaller in diabetic females. Pretreatment of diabetic males with the angiotensin-converting enzyme inhibitor quinapril reduced Cx43 lateralization and the effects of 9 mM K(+) on propagation. In conclusion, the slowing of cardiac impulse propagation in type 1 diabetes is smaller in female rats, partly due to the presence of female sex hormones. This difference is (partly) mediated by sex differences in activation of the cardiac renin-angiotensin system.
Shimoni
Yakhin
Y
Department of Physiology and Biophysics, University of Calgary, Health Sciences Centre, 3330 Hospital Dr. N.W., Calgary, AB Canada T2N 4N1. shimoni@ucalgary.ca
Emmett
Teresa
T
Schmidt
Robyn
R
Nygren
Anders
A
Kargacin
Gary
G
D000200:Action Potentials; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D018031:Connexin 43 / Q000378:metabolism*; D048909:Diabetes Complications / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D019850:Heptanol / Q000494:pharmacology; D008297:Male; D010052:Ovariectomy; D000077583:Quinapril; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System; D012737:Sex Factors; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D018031:Connexin 43; D044005:Tetrahydroisoquinolines; D019850:Heptanol; D000077583:Quinapril