PURINERGIC STIMULATION OF THE HEART - INOTROPISM AND ARRHYTHMIA

Intracellular ATP (ATP(i)) in the 10 mM range is the major source of e nergy and a susbtrate for many biochemical processes. In the mu M rang e extracellular ATP (ATP(e)), whatever co-released by nerve terminals or various eel types: platelets, endothelial or cardiac cells, modifie s many cellular activities. It binds to P2-purinergic receptors whose P2X-subtypes activate directly non specific cationic channels and P2Y subtypes involve G proteins. Like adenosine, its degradation product w hich had been up to now the matter of most studies, ATP, increases var ious 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 activ ation of the adenylyl cyclase. ATP(e) also increases both T and L type s Ca currents, In the latter case, this induces an increase in contrac tile force associated with the enhancement of Ca release by the sarcop lasmic reticulum. ATP application induces a large transient acidosis f ollowed 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 reversib ly phosphorylated on a tyrosine. Similarly the P2-purinergic stimulati on by activating tyrosine kinases increases the PLC gamma activity tha t leads to the production of inositol trisphophate (InsP3). The physio logical and pathological effects of ATP(e) are multiple. Besides the p ositive inotropism described above, ATP(e) modulates the rhythmic acti vity and may even trigger anomalous automatism in ventricular tissues as a consequence of acidosis and increase in non specific cationic con ductance. However, the major effect of ATP(e) in auricular tissues is to increase K conductances and thus to slow down basal rhythmic activi ty. ATP(e) triggers the expression of early genes c-Fos and Jun-B; it also activates several isoforms of the protein kinase C, PKC epsilon a nd PKC delta as well as p42(MAPK) and p44(MAPK). However ATP(e), in co ntrast to alpha 1-adrenergic agonists which activate the same early ge nes and kinases, does not induce cell hypertrophy. On cardiac isolated cells, the effects of ATP, are thus multiple and have been shown to d epend on the cell state. One has to anticipate much more complex respo nses in situ. In the cardiac tissues, ATP is liberated and rapidly deg raded by ectonucleotidases leading to adenosine and other nucleoside d erivates. Furthermore ATP is generally co-released by nerve terminals together with other neuromediators that will potentiate or antagonise the beneficial or deleterious physiological effects.