Stimulation purinergique et coeur : inotropisme et arythmie

Abstract

L'ATP est la source d'énergie cellulaire la plus importante. Présent en forte concentration à l'intérieur des cellules (mM) , il agit aussi sur la face extracellulaire de la membrane (ATP e) , en concentration micro molaire (/-LM) . Libéré avec les autres neurotransmetteurs par les terminaisons nerveuses, mais aussi par les cellules endothéliales et les plaquettes, son action est alors relayée par des récepteurs purinergiques spécifiques P2X et P2Y. L' ATP e /-LM déclenche un courant transitoire non sélectif pour les cations et augmente le courant calcique soutenu leau La transmission intracellulaire du signal ATP comporte une élévation de la concentration cellulaire de Ca2+ et une forte acidose transitoire (1 minute) suivie d'une alcalose. Dans les conditions physiologiques, l' ATP a une action inotrope positive et chronotrope négative sur les cellules ventriculaires. En revanche, en concentration élevée, après lésion des cellules ou ischémie, l'ATPe facilitant l'ouverture des courants potassiques hyperpolarise les cellules de la zone ischémiée et les rend non excitables, à l'inverse des cellules saines avoisinantes qu'il dépolarise, pouvant déclencher un automatisme anormal.

Intracellular ATP (ATP(i)) in the 10 mM range is the major source of energy and a susbtrate for many biochemical processes. In the muM range extracelular ATP ((ATP(e)) whatever co-released by nerve terminals or various cell types: platelets, endothelial or cardiac cells, modifies many cellular activities specific cationic channels and P2Y subtypes involve G proteins. Like adenosine, its degradation product which had been up to now the matter of most studies, ATP(e) increases various K currents. A Gi/o protein seems to be the direct link enhancing the K inward rectifyer and K(Ach) current. However, the increase in K(ATP) current which is activated by a decrease in ATP(i) results from a further subbmembrane ATP(i)-depletion as a consequence of the activation of the adenylyl cyclase. ATP(e) also increases both T and L types Ca currents. In the latter case, this induces an increase in contractile force associated with the enhancement of Ca release by the sarcoplasmic reticulum. ATP application induces a large transient acidosis followed by a sustained alcalosis, the latter could as well contribute to the positive inotropism. Acidosis is mediated by activation of the Cl/HCO3, exchanger, a band 3-like protein which is rapidly and reversibly phosphorylated on a tyrosine. Similarly the P2-purinergic stimulation by activating tyrosine kinases increases the PLCgamma activity that leads to the production of inositol trisphophate (InsP3). The physiological and pathological effects of ATP(e) are multiple. Besides the positive inotropism described above, ATP(e) modulates the rhythmic activity and may even trigger anomalous automatisim ventricular tissues as a consequence of acidosis and increase in non specific catatonic conductance. However, the major effect of ATP(e) in auricular tissues is to increase K conductances and thus to slow down basal rythmic activity. ATP(e) triggers the expression of early genes c-Fos and Jun-B; it also activates several isoforms of the protein kinase C, PKCepsilon and PKCdelta as well as p42(MAPK) and p44(MAPK). However ATP(e), in contrast to alpha1-adrenergic agonists which activate the same early genes and kinases, does not induce cell hypertrophy. On cardiac isolated cells, the effects of ATP(e) are thus multiple and have been shown to depend on the cell state. One has to anticipate much more complex responses in situ. In the cardiac tissues, ATP is liberated and rapidly degraded by ectonucleotidases leading to adenosine and other nucleoside derivates. Furthermore ATP is generally co-released by nerve terminals together with other neuromediators that will potentiate or antagonise the beneficial or deleterious physiological effects