Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

Abstract

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.

Simulations of Reduced Conduction Reserve in the Diabetic Rat Heart: Response to Uncoupling and Reduced Excitability

“…25,34 Contrary to our initial working hypothesis, the simulations showed that while reduced intercellular coupling does reduce overall CV, it does so without altering the slope of the CV vs. [K + ] o relationship. While the increased response to heptanol application in diabetic hearts appears to be clearly related to reduced intercellular coupling (above), it therefore appears that there may be an additional ''defect'' related to conduction in diabetic hearts.…”

“…25,34 This was evident as a larger slowing of conduction velocity in the diabetic hearts than in controls in response to either (1) administration of the gap junction uncoupler heptanol or (2) increasing extracellular [K + ] ([K + ] o ) to reduce cellular excitability. Based on immunohistochemistry observations, our working hypothesis is that intercellular electrical coupling in the diabetic heart is compromised due to lateralization of Cx43, rendering the lateralized Cx43 non-functional.…”

“…The work is based on the Pandit model of the rat ventricular myocyte, 26 which is the best description available to date of rat ventricular cellular electrophysiology. One obvious discrepancy between the Pandit model and our experimental data to which these simulations are compared 25,34 is that the experimental work (in whole hearts) was carried out at physiological temperature, whereas the Pandit model was designed to mimic experiments at room temperature. The impact of this on our results is expected to be minimal, given that all results are normalized before comparisons are made.…”

“…4, 28 These abnormalities have been well described in the literature and relate to attenuation of repolarizing K + currents. 35,42 Recent work from our lab 25,34 and others 6,17 has demonstrated that diabetes, in the streptozotocin-induced (STZ) rat model of type I diabetes, is also associated with abnormalities in intercellular electrical coupling. Normal ventricular function depends on rapid spread of electrical activation, resulting in synchronous contraction.…”

“…In our recent work, we have demonstrated that hearts from STZ-diabetic rats exhibit a reduced conduction reserve related to lateralization of Cx43 protein. 25,34 Accordingly, although the baseline conduction velocity in STZ-diabetic hearts is only marginally different from controls, 2 the slowing in response to further uncoupling (e.g., using the gap junction blocker heptanol) or reduced cellular excitability (by increasing extracellular K + concentration) is significantly increased in STZ hearts compared to controls.…”