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A Mathematical Model of the Slow Force Response to Stretch in Rat Ventricular Myocytes

Steven A. Niederer ^*  and Nicolas P. Smith ^* 

^* Bioengineering Institute, University of Auckland, Auckland, New Zealand; and Computing Laboratory, University of Oxford, Oxford, England

Correspondence: Address reprint requests to Nicolas P. Smith, Oxford University, Computing Laboratory, Wolfson Bldg., Parks Rd., Oxford, OX1 3QD, UK. E-mail: nic.smith{at}comlab.ox.ac.uk.

We developed a model of the rat ventricular myocyte at room temperature to predict the relative effects of different mechanisms on the cause of the slow increase in force in response to a step change in muscle length. We performed simulations in the presence of stretch-dependent increases in flux through the Na⁺-H⁺ exchanger (NHE) and exchanger (AE), stretch-activated channels (SAC), and the stretch-dependent nitric oxide (NO) induced increased open probability of the ryanodine receptors to estimate the capacity of each mechanism to produce the slow force response (SFR). Inclusion of stretch-dependent NHE & AE, SACs, and stretch-dependent NO effects caused an increase in tension following 15 min of stretch of 0.87%, 32%, and 0%, respectively. Comparing [Ca²⁺]_i dynamics before and after stretch in the presence of combinations of the three stretch-dependent elements, which produced significant SFR values (>20%), showed that the inclusion of stretch-dependent NO effects produced [Ca²⁺]_i transients, which were not consistent with experimental results. Further simulations showed that in the presence of SACs and the absence of stretch-dependent NHE & AE inhibition of NHE attenuated the SFR, such that reduced SFR in the presence of NHE blockers does not indicate a stretch dependence of NHE. Rather, a functioning NHE is responsible for a portion of the SFR. Based on our simulations we estimate that in rat cardiac myocytes at room temperature SACs play a significant role in producing the SFR, potentially in the presence of stretch-dependent NHE & AE and that NO effects, if any, must involve more mechanisms than just increasing the open probability of ryanodine receptors.

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