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Activation of purinergic P2 receptors, which are expressed in neurons and microglial cells, normally induces an increase in intracellular calcium concentration ([Ca(2+)](i)) and some of the inflammatory mediators and excitatory neurotransmitters found to be implicated in neuronal cell death observed in diabetic retinas are released in response to an increase in the [Ca(2+)](i). However, it is unknown whether hyperglycemia/high glucose has an effect in the [Ca(2+)](i) changes triggered by the activation of P2 receptors in retinal cells. Using single-cell calcium imaging studies, we found that [Ca(2+)](i) changes triggered by purinergic receptors activation, both in retinal neurons and microglial cells, were potentiated in cells that had been cultured in high glucose conditions. In retinal neurons the increase in [Ca(2+)](i) was mostly due to Ca(2+) influx through voltage sensitive calcium channels, whereas in microglial cells Ca(2+) influx occurred mainly through P2X receptor channels, while there was also a smaller component of [Ca(2+)](i) rise dependent on calcium release from intracellular stores, probably due to P2Y receptor activation. In conclusion, our results show that rat retinal neural cells cultured in high glucose conditions show increased calcium responses to P2 receptors activation. This augmented calcium response might account for the increase in the release of neurotransmitters and inflammatory mediators found in diabetic retinas and, therefore, be responsible for retinal cell death observed in the early stages of diabetic retinopathy., ((c) 2009 Elsevier B.V. All rights reserved.)