Abstract
Cytosolic Ca2+,
[Ca2+]I , has a key role in intracellular
signalling during excitation-contraction coupling (E-C coupling) in cardiac myocytes. The
sarcoplasmic reticulum (SR) is a main intracellular Ca2+ store
and the Na+-Ca2+ exchanger (NaCaX) is
a major mechanism to extrude Ca2+ for balancing the
Ca2+ influx via L-type Ca2+ channels
during excitation. Furthermore, [Ca2+]I
also affects the configuration of the action potential (AP). The present study, by
combination of animal experiments and computer simulations, investigated the roles of
[Ca2+]I, SR and NaCaX in cardiac
myocytes, in Ca2+-induced Ca2+
release (CICR) and in modulation
of APs. The following were studied: (I) the stretch-induced effects on rat atrium and the
role of [Ca2+]I in modulation of AP; (II)
the role of the SR in modulation in rat atrium by stretch; (III) the role of NaCaX; (IV)
the role of [Ca2+]I in modulation of
action potential duration (APD) in myocytes with short and long action potential duration.
In isolated rat atrial preparations, the physiological or moderate stretch stimulus
caused two- phasic rise of developed contraction, rapid and slow phases, accompanied with
slow increments of [Ca2+]I and
prolongations of action potentials durations in continuous recordings. In sustained stretch,
the APD and [Ca2+]I were all increased
significantly when intra-atrial pressure increased from 1 to 3 mmHg. In computer
simulations, employing a rat atrial model (RA model), it was found that stretch-activated
channels and increased Tn C affinity for Ca2+ alone could not
produce the changes in the
experiments. Only after both mechanisms applied to model cells, the main experimental
findings could be mimicked (I). The prolongation of APD induced by stretch in rat atrial
preparations was reversed after depleting the Ca2+ content of
the SR by application of the
SR functional inhibitors, ryanodine, thapsigargin and caffeine (II). In the computer
simulation using modified guinea pig ventricular model, the Ca2+
entry via the reversal of NaCaX was found to be accounting 25% of the total activator
Ca2+ for triggering Ca2+ release
from the SR during normal excitation. This contribution increases with elevated
[Na+]i (III). In a guinea pig ventricular
model (GPV model) and a RA model were employed for investigating the regulation of APD by
[Ca2+]I-dependent membrane currents.
Increased SR Ca2+ content produced an elevated
[Ca2+]I in both model cells, leading to
prolongation of APD in the RA model but shortening in the GPV model. Increased
[Ca2+]I enhances the NaCaX current in the
same scale in both models, but inhibits L-type Ca current much more in the GPV model than
the RA model (IV).
In conclusion, (I) Stretch-induced [Ca2+]I
increase prolongs the rat atrial AP by enhancing the NaCaX inward current. Stretch-activated
channels (SACs) and increased affinity of TnC for Ca2+ are
main general factors responsible for the variety of changes of cardiac muscles induced by
stretch. (II) The SR plays a crucial role in the modulation of myocytes by accumulating the
additional Ca2+ influx via sarcolemma during stretch. (III)
The NaCaX contributes a small part for activator Ca2+ for
calcium release from the SR during normal cardiac E-C coupling. However, this contribution
is [Na]i-dependent, and in some pathological conditions, it may be a potential factor for
cardiac arrhythmogenesis. (IV) Different effects on the NaCaX and L-type channels induced by
increased [Ca2+]I leads to the dispersion
of the change of APD in myocytes with long and short AP during inotropic interventions that
increase the [Ca2+]I.
| Identifer | oai:union.ndltd.org:oulo.fi/oai:oulu.fi:isbn951-42-6591-2 |
| Date | 27 November 2001 |
| Creators | Han, C. (Chunlei) |
| Publisher | University of Oulu |
| Source Sets | University of Oulu |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:eu-repo/semantics/publishedVersion |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess, © University of Oulu, 2001 |
| Relation | info:eu-repo/semantics/altIdentifier/pissn/0355-3191, info:eu-repo/semantics/altIdentifier/eissn/1796-220X |
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