Different paths, same destination: divergent action potential responses produce conserved cardiac fight-or-flight response in mouse and rabbit hearts

Wang, L. et al. (2019) Different paths, same destination: divergent action potential responses produce conserved cardiac fight-or-flight response in mouse and rabbit hearts. Journal of Physiology, 597(15), pp. 3867-3883. (doi: 10.1113/jp278016) (PMID:31215643)

Abstract

Sympathetic activation of the heart results in positive chronotropy and inotropy, which together rapidly increase cardiac output. The precise mechanisms that produce the electrophysiological and Ca2+ handling changes underlying chronotropic and inotropic responses have been studied in detail in isolated cardiac myocytes. However, few studies have examined the dynamic effects of physiological sympathetic nerve activation on cardiac action potentials (APs) and intracellular Ca2+ transients (CaTs) in the intact heart. Here, we performed bilateral sympathetic nerve stimulation (SNS) in fully innervated, Langendorff‐perfused rabbit and mouse hearts. Dual optical mapping with voltage‐ and Ca2+‐sensitive dyes allowed for analysis of spatio‐temporal AP and CaT dynamics. The rabbit heart responded to SNS with a monotonic increase in heart rate (HR), monotonic decreases in AP and CaT duration (APD, CaTD), and a monotonic increase in CaT amplitude. The mouse heart had similar HR and CaT responses; however, a pronounced biphasic APD response occurred, with initial prolongation (50.9 ± 5.1 ms at t = 0 s vs. 60.6 ± 4.1 ms at t = 15 s, P < 0.05) followed by shortening (46.5 ± 9.1 ms at t = 60 s, P = NS vs. t = 0). We determined the biphasic APD response in mouse was partly due to dynamic changes in HR during SNS and was exacerbated by β‐adrenergic activation. Simulations with species‐specific cardiac models revealed that transient APD prolongation in mouse allowed for greater and more rapid CaT responses, suggesting more rapid increases in contractility; conversely, the rabbit heart requires APD shortening to produce optimal inotropic responses. Thus, while the cardiac fight‐or‐flight response is highly conserved between species, the underlying mechanisms orchestrating these effects differ significantly.

• Item Type: Articles
• Additional Information: This work was supported by the American Heart Association grants 15SDG24910015 (E.G.) and 16GRNT30960054 (C.M.R.); the UC Davis School of Medicine Dean's Fellow award (E.G.); the National Institutes of Health (NIH) Stimulating Peripheral Activity to Relieve Conditions grants 1OT2OD023848‐01 and 1OT2OD026580‐01 (E.G. and C.M.R.); the National Heart, Lung, and Blood Institute R01HL131517 and R01HL141214 (E.G.), R01HL111600 (C.M.R.), and K99HL138160 (S.M.); the UC Davis Academic Federation Professional Development Award (LW) and British Heart Foundation Programme Grant RG/17/3/32774 (G.A.N.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Myles, Dr Rachel
• Authors: Wang, L., Morotti, S., Tapa, S., Francis Stuart, S. D., Jiang, Y., Wang, Z., Myles, R. C., Brack, K. E., Ng, G. A., Bers, D. M., Grandi, E., and Ripplinger, C. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of Physiology
• Publisher: Wiley
• ISSN: 0022-3751
• ISSN (Online): 1469-7793
• Published Online: 19 June 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Journal of Physiology 597(15): 3867-3883
• Publisher Policy: Reproduced in accordance with the publisher copyright policy