V entricular electric propagation is governed by activation sequence, electric properties of the myocardial syncytium, and anatomy of the ventricular wall.1,2 Time course and rate of propagation of the action potential (AP) depends on ionic current flow across sarcolemmal membranes and the electric resistance and capacitance of nearby myocardium. 3 These factors are heterogeneous across the ventricular wall; because of polarized gap junction distribution, intercellular resistance depends on myocardial fiber orientation 4 ; electrotonic load at any given point in the myocardium depends on the activation sequence and distance from structural features, such as the epicardial surface. In addition, ion channel expression is heterogeneous in the apex-base 5 and endocardial-epicardial axes. 6 Therefore, the rate of depolarization of the AP reflects myocardial excitability. However, the influence of activation sequence on AP upstroke is still a matter of debate. 7,8 Although continuous cable theory predicts that a higher conduction velocity (CV) is associated with higher maximal upstroke velocity (dV/dt max ), 9 on the surface of isolated cardiac muscle preparations longitudinal propagation results in faster CV but lower dV/dt max relative to transverse propagation. 10 These observations were explained by (1) predominantly axial connexin distribution and (2) arrangement of capillary vessels parallel to the longitudinal axis of the cells.11 This has been challenged by computational modeling, which suggests that differences in upstroke characteristics are limited to myocardium close to the epicardial surface.7 Until now, this could not be verified experimentally because of the technical difficulty associated with accurate transmembrane © 2013 American Heart Association, Inc. Original Article Circ Arrhythm ElectrophysiolBackground-Electric excitability in the ventricular wall is influenced by cellular electrophysiology and passive electric properties of the myocardium. Action potential (AP) rise time, an indicator of myocardial excitability, is influenced by conduction pattern and distance from the epicardial surface. This study examined AP rise times and conduction velocity as the depolarizing wavefront approaches the epicardial surface. Methods and Results-Two-photon excitation of di-4-aminonaphthenyl-pyridinum-propylsulfonate was used to measure electric activity at discrete epicardial layers of isolated Langendorff-perfused rabbit hearts to a depth of 500 μm. Endoto-epicardial wavefronts were studied during right atrial or ventricular endocardial pacing. Similar measurements were made with epi-to-endocardial, transverse, and longitudinal pacing protocols. Results were compared with data from a bidomain model of 3-dimensional (3D) electric propagation within ventricular myocardium. During right atrial and endocardial pacing, AP rise time (10%-90% of upstroke) decreased by ≈50% between 500 and 50 μm from the epicardial surface, whereas conduction velocity increased and AP duration was only slightly shorter (≈4%). The...
We describe a novel two-photon (2P) laser scanning microscopy (2PLSM) protocol that provides ratiometric transmural measurements of membrane voltage (V m ) via Di-4-ANEPPS in intact mouse, rat and rabbit hearts with subcellular resolution. The same cells were then imaged with Fura-2/AM for intracellular Ca 2+ recordings. Action potentials (APs) were accurately characterized by 2PLSM vs microelectrodes, albeit fast events (<1ms) were sub-optimally acquired by 2PLSM due to limited sampling frequencies (2.6kHz). The slower Ca 2+ transient (CaT) time course (>1ms) could be accurately described by 2PLSM. In conclusion, V m -and Ca 2+ -sensitive dyes can be 2P excited within the cardiac muscle wall to provide AP and Ca 2+ signals to ~400μm.Abstract Figure: 2P-excited images of Di-4-ANEPPS-and Fura-2/AM-loaded myocardium including the resultant AP and CaT extracted from the presented protocols.
The uterus and heart share the important physiological feature whereby contractile activation of the muscle tissue is regulated by the generation of periodic, spontaneous electrical action potentials (APs). Preterm birth arising from premature uterine contractions is a major complication of pregnancy and there remains a need to pursue avenues of research that facilitate the use of drugs, tocolytics, to limit these inappropriate contractions without deleterious actions on cardiac electrical excitation. A novel approach is to make use of mathematical models of uterine and cardiac APs, which incorporate many ionic currents contributing to the AP forms, and test the cell-specific responses to interventions. We have used three such models—of uterine smooth muscle cells (USMC), cardiac sinoatrial node cells (SAN), and ventricular cells—to investigate the relative effects of reducing two important voltage-gated Ca currents—the L-type (ICaL) and T-type (ICaT) Ca currents. Reduction of ICaL (10%) alone, or ICaT (40%) alone, blunted USMC APs with little effect on ventricular APs and only mild effects on SAN activity. Larger reductions in either current further attenuated the USMC APs but with also greater effects on SAN APs. Encouragingly, a combination of ICaL and ICaT reduction did blunt USMC APs as intended with little detriment to APs of either cardiac cell type. Subsequent overlapping maps of ICaL and ICaT inhibition profiles from each model revealed a range of combined reductions of ICaL and ICaT over which an appreciable diminution of USMC APs could be achieved with no deleterious action on cardiac SAN or ventricular APs. This novel approach illustrates the potential for computational biology to inform us of possible uterine and cardiac cell-specific mechanisms. Incorporating such computational approaches in future studies directed at designing new, or repurposing existing, tocolytics will be beneficial for establishing a desired uterine specificity of action.
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