Extracellular purines and pyrimidines have major effects on cardiac rhythm and contraction. ATP/UTP are released during various physiopathological conditions such as ischemia and, despite degradation by ectonucleotidases, their interstitial concentrations can markedly increased, a fact that is clearly associated with arrhythmia. In the present whole-cell patch-clamp analysis on ventricular cardiomyocytes isolated from various mammalian species, ATP and UTP elicited a sustained, non-selective cationic current, I_ATP. UDP was ineffective while BzATP was active, suggesting that P2Y₂ receptors are involved. IATP resulted from the binding of ATP4- to P2Y₂ purinoreceptors. IATP was maintained after ATP removal in the presence of GTPS and was inhibited by U-73122, a phospholipase C inhibitor. Single channel openings are rather infrequent under basal conditions. ATPmarkedly increased opening probability, an effect prevented by U-73122. Two main conductance levels of 14 and 23 pS were easily distinguished. Similarly, in Fura 2-loaded cardiomyocytes Mn²⁺ quenching and Ba²⁺ influx were significant only in the presence of ATP or UTP. Adult rat ventricular cardiomyocytes expressed TRPC1, 3, 4, 7 mRNA and the TRPC3 and TRPC7 proteins that co-immunoprecipitated. Finally, the anti-TRPC3 antibody added to the patch pipette solution inhibited I_ATP. In conclusion, activation of P2Y₂ receptors, via a G-protein and stimulation of PLC, induces the opening of heteromeric TRPC3/7 channels leading to a sustained, non-specific cationic current. Such a depolarising current could induce cell automaticity and trigger the arrhythmic events during an early infarct when ATP/UTP release occurs. These results emphasize a new, potentially deleterious, role of TRPC channel activation.