Experimental results have shown that action potential (AP) conduction in ventricular tissue from streptozotocin-diabetic (STZ) rats is compromised. This was manifest as increased sensitivity of conduction velocity (CV) to the gap junction uncoupler heptanol, as well as increased sensitivity of CV to reduced cellular excitability due to elevated extracellular K(+) concentration, in the STZ hearts. This "reduced conduction reserve" has been suggested to be due to lateralization of connexin43 (Cx43) proteins, rendering them nonfunctional, resulting in compromised intercellular electrical coupling. In this study, we have used computer simulations of one-dimensional AP conduction in a model of rat ventricular myocytes to verify this interpretation. Our results show that compromised intercellular coupling indeed reduces conduction reserve and predict a response to gap junction uncoupling with heptanol that is consistent with experiments. However, our simulations also show that compromised intercellular coupling is insufficient to explain the increased sensitivity to reduced cellular excitability. A thorough investigation of possible underlying mechanisms, suggests that subtle alterations in the voltage-dependence of steady-state gating for the Na(+) current (I (Na)), combined with compromised intercellular coupling, is a likely mechanism for these observations.
Conduction velocity is dependent on two main factors: intercellular electrical coupling and cellular electrical excitability. There is significant redundancy, 'conduction reserve', in these parameters such that significant reduction in the conduction velocity of the action potential requires either a severe change in one of these parameters or a combined change in both parameters. Studies in diabetic rat hearts have shown a significant reduction in the conduction reserve and it was hypothesized that this is mainly due to the lateralization of the gap junction protein connexin 43 (Cx43). To gain a better understanding of the effect of reduced intercellular coupling, a rat ventricle myocyte model was used to simulate propagation along a strand of cells. Simulations were performed to assess the effect of reduction of intercellular conductance on the conduction velocity. As the conductance of the gap junction decreased a significant reduction in the conduction velocity was observed. The relationship between conduction velocity and intercellular coupling became steeper with decreasing coupling, such that conduction velocity became increasingly sensitive to further uncoupling. This is consistent with experimental results, in which application of the gap junction uncoupler heptanol caused a larger conduction slowing in diabetic hearts than in controls.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.