Abstract
The sympathetic nervous system is essential for maintenance of cardiac function via activation of post-junctional adrenergic receptors. Prolonged adrenergic receptor activation, however, has deleterious long-term effects leading to hypertrophy and the development of heart failure. Here we investigate the effect of chronic adrenergic receptors activation on excitation-contraction coupling (ECC) in ventricular cardiomyocytes from a previously characterized mouse model of chronic sympathetic hyperactivity, which are genetically deficient in the adrenoceptor α2A and α2C genes (ARDKO). When compared to wild-type (WT) cardiomyocytes, ARDKO displayed reduced fractional shortening (~33%) and slower relaxation (~20%). Furthermore, ARDKO cells exhibited several electrophysiological changes such as action potential (AP) prolongation (~50%), reduced L-type calcium channel (LCC) current (~33%), reduced outward potassium (K+) currents (~30%), and increased sodium/calcium exchanger (NCX) activity (~52%). Consistent with reduced contractility and calcium (Ca2+) currents, the cytosolic Ca2+ ([Ca2+]i) transient from ARDKO animals was smaller and decayed slower. Importantly, no changes were observed in membrane resting potential, AP amplitude, or the inward K+ current. Finally, we modified our existing cardiac ECC computational model to account for changes in the ARDKO heart. Simulations suggest that cellular changes in the ARDKO heart resulted in variable and dyssynchronous Ca2+-induced Ca2+ release therefore altering [Ca2+]i transient dynamics and reducing force generation. In conclusion, chronic sympathetic hyperactivity impairs ECC by changing the density of several ionic currents (and thus AP repolarization) causing altered Ca2+ dynamics and contractile activity. This demonstrates the important role of ECC remodeling in the cardiac dysfunction secondary to chronic sympathetic activity.
Highlights
The present study explored the role of chronic sympathetic hyperactivity (CSH) in the remodeling of the excitation-contraction coupling (ECC)
The adrenergic receptor double knock-out (ARDKO) animal model is well suited for the study of the role of sympathetic tonus increase in development and progression of cardiac disease. Using this ARDKO animal model we investigated the influence of Chronic sympathetic hyperactivity (CSH) on cardiac ECC and found that CSH induces an electrochemical remodeling in ventricular cardiomyocytes (VCMs) which included action potential (AP) prolongation, altered ion currents, and impaired cellular contractility and Ca2+ handling
Experiments were performed using 7 month old mice, when cardiovascular dysfunction has been reported[6,18,19]. Similar to these previous findings, we observed that ARDKO animals displayed increased heart rate (HR) and mean arterial pressure (MAP) secondary to the chronic sympathetic hyperactivity
Summary
All experimental procedures were conducted according to guidelines from both the Brazilian. Society of Laboratory Animal Science (SBCAL) and the United States’ National Institutes of Health (NIH) Animal Care Guide. The project was approved to the Animal Use Ethics Committee of the Federal University of Minas Gerais (CEUA - UFMG) without restriction to the proposed procedures (Protocol No 340/2013). Two animal groups were used, the ARDKO (males, 3 and 7 months old) in C57BL6/J genetic background, and wild-type (WT) controls (males, 3 and 7 months old). At the age of seven months, ARDKO mice had cardiac dysfunction associated with exercise intolerance and a higher mortality rate[6,8]. The animals were obtained from the School of Physical Education and Sport, University of São Paulo, São Paulo, SP, Brazil
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