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Model-based analysis of ß-adrenergic modulation of I Ks in the guinea-pig ventricle

Biomedical Engineering Laboratory DEIS, University of Bologna Cesena, Italy. Dept of Biotechnology and Bioscience University of Milano Bicocca Milano, Italy. Model-based analysis of ß-adrenergic modulation of I Ks in the guinea-pig ventricle. Stefano Severi.

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Model-based analysis of ß-adrenergic modulation of I Ks in the guinea-pig ventricle

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  1. Biomedical Engineering Laboratory DEIS, University of Bologna Cesena, Italy Dept of Biotechnology and Bioscience University of Milano Bicocca Milano, Italy Model-based analysis of ß-adrenergic modulation of IKs in the guinea-pig ventricle Stefano Severi C3MIG

  2. Results: Model-based analysis C3MIG

  3. Results: Model based analysis of the effects of β-adrenergic stimulation Deactivation C3MIG

  4. C C C O * * * * C C C O                   Discussion: Model based analysis of mechanisms of ISO effects s increasenot possible gKsincreasenot likely ( single channel exp.) Po increaselikely  good fitting Modal gating possible, more complex σ: channel density gKs: unitary channel conductance ISO-induced increase in the maximal steady-state IKs: C3MIG

  5. Discussion: Model based analysis of mechanisms of ISO effects No way for ISO to further increase the number of open channels • Increase in gKs • Modal gating: a sub-population of channels that neveropen without phosphorylation Silva & Rudy formulation: C3MIG

  6. Discussion: Model based analysis of mechanisms of ISO effects • The overall channel population interact with ISO, • ISO changes IKs kinetic properties allowing a greater number of concurrent open channels C3MIG

  7. Discussion: Model based analysis of mechanisms of ISO effects C3MIG

  8. (s-1) (s-1) 15  60  7.5 30   0 0 0 -100 -50 0 50 -100 -50 0 50 (mV) Discussion: Model based analysis of mechanisms of ISO effects ISO CTR C3MIG

  9. Available reserve Istantaneous current Discussion: Model based analysis of mechanisms of ISO effects C3MIG

  10. (s-1) 15  7.5  0 0 -100 -50 0 50 Discussion: Model based analysis of mechanisms of ISO effects What’s the cause of ISO-induced AR increase? Slowed transition to Zone 2? ISO CTR C3MIG

  11. Results: Model-based analysis C3MIG

  12. Discussion: Model based analysis of mechanisms of ISO effects • A “bottleneck effect” due to a larger number of open channels • the overall kinetic properties of the current not only depend on the transition rates but also on the occupancy distribution • In this framework, results on activation restitution are consistent with the hypothesis of an effect of ISO on the number of open channels rather than an increase in the single channel conductance C3MIG

  13. Results: Model-based analysis C3MIG

  14. (s-1) (s-1) 15  60  7.5 30   0 0 0 -100 -50 0 50 -100 -50 0 50 (mV) DiscussionStudy limitations • The model is a simplification of actual processes involved in ß-adrenergic modulation of IKs • Parameters were determined by nonlinear optimization. Although we incorporated several experiments, there may be different parameters that also reproduce channel properties. • Nevertheless it is also worth to note that all the experimental effects of ISO were reproduced by essentially acting on only three over 8 kinetic rates b slightly affected g, d, w, y not affected ISO CTR C3MIG

  15. DiscussionStudy limitations exponential fitting of (re)activation • It is not a bi-exponential! C3MIG

  16. DiscussionStudy limitations • Too much, 5, parameters to be estimated: C3MIG

  17. DiscussionStudy limitations  To have a more direct and reliable comparison with experimental data it would be better to skip the exponential fitting and simply measure the time required to activation: t90 t50 t10 C3MIG

  18. Future work • We are incorporating the IKs model in a whole cell model (LRd) • ß-adrenergic effects on many cellular processes should be incorporated C3MIG

  19. Conclusions • All the changes in IKs caused by β-AR stimulation can be reproduced by the same model structure which fits control data • The increase in maximal steady state current can be explained mostly by redistribution of occupancies within the same chain of states. Neither a separate channel population, nor “modal gating” are required • ß-adrenergic stimulation accelerates reactivation by increasing the transient accumulation in states close to open during the diastolic interval • By regulating the access to a large reserve of usually closed channels ß-adrenergic modulation can be crucial in determining the contribution of IKs to cardiac electrophysiological response in humans C3MIG

  20. Biomedical Engineering Laboratory DEIS, University of Bologna Cesena, Italy Dept of Biotechnology and Bioscience University of Milano Bicocca Milano, Italy Contributors Antonio Marcella Zaza Rocchetti Stefano Cristiana Severi Corsi C3MIG

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