Astrocytes use ATP as a signaling molecule to communicate among themselves and with neighboring neurons.
47 Various stimuli have been shown to elicit ATP release from astrocytes, including mechanical stimulation,
47,48 osmotic stress,
49,50 ischemic stress mimicked by oxygen-glucose deprivation,
51 and receptor agonists such as UTP,
52 norepinephrine,
53 and glutamate.
54,55 A relatively small hydrostatic pressure challenge of 3.5 cm H
2O (2.5 mm Hg) has been reported to release ATP in urinary bladder epithelium,
56 whereas a higher pressure challenge of 700 cm H
2O (50 mm Hg) caused ATP release by guinea pig ureter epithelium.
57 Hydrostatic pressure of 20 mm Hg applied to the retina in an eyecup preparation has been shown to increase ATP concentration by threefold in the vitreous.
58 However, in the whole retina study, it was not possible to pinpoint the source of ATP to a particular cell type because ATP can be released from retinal ganglion cells,
59 Müller cells,
60,61 microglia,
62 and retinal pigment epithelium.
63 Thus, although there is evidence that astrocytes release ATP under many different conditions, leading to purinergic P2 receptor-mediated calcium signaling in the same or neighboring cell,
64 there was no evidence for such an underlying mechanism in the observed pressure-evoked calcium increase. Suramin, a broad-spectrum purinergic receptor antagonist, failed to diminish the pressure-induced calcium increase. However, effective concentrations of suramin are higher for some P2 receptors, particularly the rodent P2 × P7 receptor, in which an inhibitory effect of suramin less than 300 μM is uncommon.
65,66 Here, we targeted ATP-mediated calcium release. Such calcium mobilization is usually mediated by the activation of P2Y receptors.
67 Suramin is a potent antagonist at the P2Y receptor.
68