Propagation of the cardiac impulse in the diabetic rat heart: reduced conduction reserve.
Diabetes mellitus is a growing epidemic with severe cardiovascular complications. Although much is known about mechanical and electrical cardiac dysfunction in diabetes, few studies have investigated propagation of the electrical signal in the diabetic heart and the associated changes in intercellular gap junctions. This study was designed to investigate these issues, using hearts from control and diabetic rats. Diabetic conditions were induced by streptozotocin (STZ), given i.v. 7-14 days before experiments. Optical mapping with the voltage-sensitive dye di-4-ANEPPS, using hearts perfused on a Langendorff apparatus, showed little change in baseline conduction velocity in diabetic hearts, reflecting the large reserve of function. However, both the gap junction uncoupler heptanol (0.5-1 mM) and elevated potassium (9 mM, to reduce cell excitability) produced a significantly greater slowing of impulse propagation in diabetic hearts than in controls. The maximal action potential upstroke velocity (an index of the sodium current) and resting potential was similar in single ventricular myocytes from control and diabetic rats, suggesting similar electrical excitability. Immunoblotting of connexin 43 (Cx43), a major gap junction component, showed no change in total expression. However, immunofluorescence labelling of Cx43 showed a significant redistribution, apparent as enhanced Cx43 lateralization. This was quantified and found to be significantly larger than in control myocytes. Labelling of two other gap junction proteins, N-cadherin and beta-catenin, showed a (partial) loss of co-localization with Cx43, indicating that enhancement of lateralized Cx43 is associated with non-functional gap junctions. In conclusion, conduction reserve is smaller in the diabetic heart, priming it for impaired conduction upon further challenges. This can desynchronize contraction and contribute to arrhythmogenesis.
Nygren
A
A
Department of Electrical and Computer Engineering, University of Calgary, Alberta, Canada.
Olson
M L
ML
Chen
K Y
KY
Emmett
T
T
Kargacin
G
G
Shimoni
Y
Y
D000818:Animals; D018031:Connexin 43 / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D017629:Gap Junctions / Q000502:physiology; D006329:Heart Conduction System / Q000502:physiology*; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D018031:Connexin 43