By Laetitia Mercadieu, PhysioStim.
Dated: 1/1/2008
A model on isolated cardiomyocytes offers a global vision of adverse effects on cardiovascular system.
By Laetitia Mercadieu, PhysioStim
The heart is constituted of three tunics: the pericardium, extracellular serous tunic; the myocardium, middle depth, muscular tunic; and the endocardium, mucous membrane inside. The myocardium is a striated muscle with the sarcoplasm of the cells rich in mitochondrias. The myocardial capillary network is dense, and it is symbolic of an intensive aerobia metabolism. It represents the muscular layer of the heart.
Cells are set up in successive layers covering the different cardiac rooms organizing in a spiral. During a cycle, each parts of the myocardium are in turn in activity or in rest. If a piece of the myocardial tissue is stimulated, the simultaneous recording of the mechanic activity and cellular electrical activity shows that the action potential duration is at least equal to that of the ascendant phase.
The myocardium is composed of three types of cells:
- Myocardial cells (majority)
- Nodal cells (generating and conducting the action potential)
- Endocrine myocardial cells
The myocardial prioritary cells are focused when studying isolated myocytes, which are cells fitted each with intracellular bridge “gap junction”. The interest in working on the isolated myocytes is that they are responsible for the “mechanical work” of the heart (contraction of the muscular structure).
The properties of the myocardial cells are inevitably excitable cells because of their membrane’s content, contractility, conductivity and automaticity. Concurrently, the action potential recording on the Purkinje fiber (nodal cells, performed in PhysioStim) is focused on the conduction of the cardiac signal in the heart to the ventricle (myocytes).
Techniques
The cardiomyocytes are obtained with an enzymatical dissolution (collagenase, protease) of a whole heart, which was chilly dissected. The cardiomyocytes at rest are polarized. Consequently, there are differences of potential on both sides the membrane (- 80 mV for cardiomyocytes).
We can have two approaches with this model of isolated cardiomyocytes:
- Current clamp: a voltage is imposed with stimulation and a current is recorded.
- Voltage clamp: a current is imposed to the cell and the voltage is recorded.
A specific study on ionic channels would be performed with specific inhibitor of channel (ex:4-AP blocks K+ current).
Cardiac issues
The cardiac rhythm starts in the in the sinusal node (grouping of nervous cells located in the wall of the right atria). This node generates an excitation that creates the cardiac contraction. This impulse is going to progress through the different cardiac structures and supply the cardiac work.
Myocardial tissue is specialized in propagating the cardiac impulse and synchronizing the movements of the different parts of the heart. The disorders of the rhythm are called arrhythmias and expressed as:
- Bradycardia: sudden and temporary decrease of the rhythm,
- Tachycardia: speeding up of the rhythm,
- Atrial extrasystoles: variations of the rhythm without risk,
- Ventricular fibrillation: very fast and disorder contraction of the ventricle that leads to an irrigation failure of the essential organs, and
- Ventricular extrasystoles: anarchic contraction of the ventricle.
These arrhythmias testify to the importance of study at an early stage with an appropriate predictive model of the adverse effect that the drug might have.
In spite of cardiac issues, this model on isolated cardiomyocytes provides a global vision of adverse effects on cardiovascular systems, and excludes at an early stage drugs that prolong QT dangerously, thus avoiding their application for marketing authorization.
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