Abstract
Stretch of the cardiac muscle activates several physiological
processes leading to changes in the function of the muscle. These
changes include increase of the contraction force accompanied by
changes in the intracellular calcium concentration. This phenomenon
is known as Frank-Starling relation of the heart. In addition to
this, stretch also influences the membrane voltage of individual myocytes
predisposing the cardiac muscle to arrhythmias. In atrial muscle
stretch augments the secretion of the atrial natriuretic peptide
(ANP). Although several cellular components are known to be sensitive
to mechanical stimulus the precise mechanisms participating to
these stretch-induced changes are not known in detail. Further
it is not known if these changes are causally related or if they
share a common causal factor. This research was aimed to study
the stretch-induced changes in the rat atrium. The possible interactive
mechanisms were studied by recording intracellular action potentials,
changes in the intracellular calcium concentration, contraction
force and ANP secretion during stretch. The plausible mechanosensitive
cellular components were incorporated into a mathematical model
that was used to further study the mechanisms. The role of intracellular
acidosis as a possible modulator of the mechanotransduction was
of special interest.
In isolated rat left atrium moderate stretch produced by increasing
the intra-atrial pressure increased the contraction force in a
biphasic manner. The immediate increase of the force was caused by
altered properties of the contractile element, but the following
slow increase was accompanied by an increase of the Ca2+ transient.
These changes were followed by lengthening of the late phase of
action potentials and augmented secretion of the ANP. Intensive
sustained stretch was also found to induce delayed afterdepolarizations
(DADs). Gadolinium (Gd3+), blocker of
stretch-activated ion channels reduced the stretch-dependent activation
of the contraction and inhibited the stretch-induced DADs. The
mathematical model simulated the experimental findings at best
when stretch-activated channel (SA-channel) activation and increased
troponin-C affinity were used to mimic the stretch. The modelling
data suggested that the SA-channel current increases the sarcoplasmic reticulum
calcium content in a time dependent manner leading to Ca2+ transient
augmentation during systole. Bigger Ca2+ transients
induce a depolarizing current during the late phase of the action
potential (AP) repolarization via the Na+/Ca2+ exchanger
causing the lengthening of the action potentials. A small reduction
of the intracellular pH (0.18 units) with 20 mM propionate was
found to modulate the stretch-induced changes in the rat atrium.
Acidosis leads to an increase in the diastolic [Ca2+]i during
stretch, inhibits the stretch-induced changes in action potentials
and slows down the contraction development during stretch by inhibiting
the fast component of the force increase. These changes in E-C-coupling
(excitation-contraction-coupling) were accompanied by a simultaneous
augmentation of the ANP secretion. Furthermore, it was shown that
contraction force and diastolic [Ca2+]i of
the stretched tissue are more sensitive to acidosis than in non-stretched
tissue.
In conclusion, the stretch-induced changes in rat atrial myocytes
are mediated by at least two mechanisms; stretch-activated Ca2+ influx
and change in the properties of the contractile element. The action
potential changes can be largely explained by modulation of the
membrane voltage by intracellular calcium via Na+/Ca2+-exchanger.
The co-occurrence of the changes in the [Ca2+]i and
ANP secretion suggests that the stretch-induced ANP secretion can
be mediated by [Ca2+]i.
| Identifer | oai:union.ndltd.org:oulo.fi/oai:oulu.fi:isbn951-42-5183-0 |
| Date | 23 March 1999 |
| Creators | Tavi, P. (Pasi) |
| 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, 1999 |
| Relation | info:eu-repo/semantics/altIdentifier/pissn/0355-3221, info:eu-repo/semantics/altIdentifier/eissn/1796-2234 |
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