Role of P2 receptors in Cerebral Vasospasm
Introduction: Extracellular ATP activates P2 receptors to increase intracellular Ca2+, to contract cerebral arteries, and to induce vasospasm in animals. This study examined the mRNA expression of P2 receptors in a rat double hemorrhage model and explored the therapeutic role of P2 receptor antagonists in a dog double hemorrhage model. Methods: One hundred SD rats were divided into five groups to undergo double hemorrhage by injecting autologous arterial blood into cisterna magna on day 0 and 2. Rats were sacrificed on day 3, 5 or 7. In sham group, rats were injected with saline. In control group, no surgery was conducted. Basilar arteries were harvested for mRNA isolation and RT-PCR or were fixed for transmission electron microscopy (TEM). Eighteen dogs were divided into three groups to have double hemorrhage and sacrificed on day 7. Two groups were treated, intracisternally, with P2 receptor antagonist suramin (selective for P2Y and P2X) or PPADS (selective for P2X1) (30 μM) from day 3–6. Angiograph was performed before blood injection and before sacrifice. The basilar arteries were collected for TEM. Results: Mild to moderate vasospasm (30–40% reduction) was observed on day 3–7 in rats. The mRNA expression of P2X1 receptor was down-regulated (P<0.05) on day 3 and recovered on day 5 and 7. P2Y1 and P2Y2 receptors were up-regulated (P<0.05) on day 5 and remain elevated on day 7. No changes were observed in the shame group. Severe vasospasm was observed on day 7 in dogs. P2 receptor antagonist Suramin but not PPADS significantly reversed (P<0.01, ANOVA) vasospasm in dogs. Discussion: P2Y1 and P2Y2, but not P2X1, may be involved in cerebral vasospasm. Up-regulation of P2Y receptor may enable ATP to produce contraction at low concentrations. Suramin reduced vasospasm probably by blocking P2Y receptors.