Mechanism of extracellular ATP-induced depolarization in rat isolated ventricular cardiomyocytes.
Adenosine triphosphate (ATP) is released during neural stimulation and cardiac hypoxia and several mechanisms of its action have been reported in different tissues. ATP stimulates P1 and P2 purinergic receptors; it also activates receptor-operated channels and increases membrane permeability to small ions. In single rat ventricular cells under whole-cell patch-clamp, a stepwise application of ATP in the micromolar range affects the resting potential and membrane currents through an entirely novel mechanism of action which involves several steps. Extracellular ATP induces an inward current and depolarization of the cell, leading to automaticity. The inward current is non-specific for cations, its reversal potential is around -5 mV. The conductance change evoked by ATP is suppressed by 4,4-diisothiocyanostilbene 2,2-disulphonic acid (DIDS) and low-chloride media and is prolonged by adding intracellular bicarbonate. These effects are specific for ATP in the presence of magnesium and are not evoked by a non-hydrolysable analogue of ATP or in the presence of vanadate. Other nucleotides are ineffective. We propose that ATP hydrolysis activates the chloride/bicarbonate (Cl-/HCO3-) exchanger. The induced local acidification could then increase intracellular free calcium and as a consequence, increases the sarcolemmal conductance. Thus, a sudden release of ATP in pathological conditions would induce a depolarization which could generate ventricular arrhythmias.
Scamps
F
F
Laboratoire de Physiologie Cellulaire Cardiaque, INSERM U-241, Université Paris-Sud, Orsay, France.
Vassort
G
G
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology / Q000031:analogs & derivatives; D004553:Electric Conductivity; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D051381:Rats; D016276:Ventricular Function
D002352:Carrier Proteins; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D004533:Egtazic Acid; D000255:Adenosine Triphosphate; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D002118:Calcium