Abstract
Our mathematical model of the rat ventricular myocyte (Pandit et al.,
2001) was utilized to explore the ionic mechanism(s) that underlie
the altered electrophysiological characteristics associated with
the short-term model of streptozotocin-induced, type-I diabetes.
The simulations show that the observed reductions in the Ca$^2+$-independent
transient outward K$^+$ current (I(t)) and the steady-state outward
K$^+$ current (I(ss)), along with slowed inactivation of the
L-type Ca$^2+$ current (I(CaL)), can result in the prolongation
of the action potential duration, a well-known experimental finding.
In addition, the model demonstrates that the slowed reactivation
kinetics of I(t) in diabetic myocytes can account for the more pronounced
rate-dependent action potential duration prolongation in diabetes,
and that a decrease in the electrogenic Na$^+$-K$^+$ pump
current (I(NaK)) results in a small depolarization in the resting
membrane potential (V(rest)). This depolarization reduces the availability
of the Na$^+$ channels (I(Na)), thereby resulting in a slower
upstroke (dV/dt(max)) of the diabetic action potential. Additional
simulations suggest that a reduction in the magnitude of I(CaL),
in combination with impaired sarcoplasmic reticulum uptake can lead
to a decreased sarcoplasmic reticulum Ca$^2+$ load. These factors
contribute to characteristic abnormal Ca$^2+$(i) homeostasis
(reduced peak systolic value and rate of decay) in myocytes from
diabetic animals. In combination, these simulation results provide
novel information and integrative insights concerning plausible ionic
mechanisms for the observed changes in cardiac repolarization and
excitation-contraction coupling in rat ventricular myocytes in the
setting of streptozotocin-induced, type-I diabetes.
- 1,
- 12547767
- action
- and
- animals,
- calcium
- calcium,
- cardiac,
- cardiovascular,
- channels,
- comparative
- computer
- diabetes
- experimental,
- gov't,
- heart
- l-type,
- mellitus,
- models,
- myocytes,
- non-u.s.
- of
- p.h.s.,
- potassium,
- potentials,
- rats,
- reproducibility
- research
- results,
- sensitivity
- simulation,
- sodium
- sodium,
- specificity,
- streptozocin,
- study,
- support,
- type
- u.s.
- ventricles,
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