Abstract
Hypercapnia induces potent vasodilation in the cerebral circulation. Although it has long been known that prostanoids participate in the cerebrovascular effects of hypercapnia, the role of prostaglandin E2 (PGE2) and PGE2 receptors have not been fully investigated. In this study, we sought to determine whether cyclooxygenase-1 (COX-1)-derived PGE2 and EP1 receptors are involved in the cerebrovascular response induced by hypercapnia. Cerebral blood flow (CBF) was recorded by laser-Doppler flowmetry in the somatosenasory cortex of anesthetized male EP1-/- mice and wild type (WT) littermates. In WT mice, neocortical application of the EP1 receptor antagonist SC-51089 attenuated the increase in CBF elicited by systemic hypercapnia (pCO2 = 50–60 mmHg). SC-51089 also attenuated the increase in CBF produced by neocortical treatment of arachidonic acid or PGE2. These CBF responses were also attenuated in EP1-/- mice. In WT mice, the COX-1 inhibitor SC-560, but not the COX-2 inhibitor NS-398, attenuated the hypercapnic CBF increase. Neocortical application of exogenous PGE2 restored the attenuation in resting CBF and the hypercapnic response induced by SC-560. In contrast, exogenous PGE2 failed to rescue the attenuation both in WT mice induced by SC-51089 and EP1-/- mice, attesting to the obligatory role of EP1 receptors in the response. These findings indicate that the hypercapnic vasodilatation depends on COX-1-derived PGE2 acting on EP1 receptors and highlight the critical role that COX-1-derived PGE2 and EP1 receptors play in the hypercapnic regulation of the cerebral circulation.
Highlights
Cerebral blood vessels are highly sensitive to changes in arterial partial pressure of carbon dioxide
prostaglandin E2 (PGE2) EP1 receptors are required for the increase in Cerebral blood flow (CBF) induced by hypercapnia In wild type (WT) mice, neocortical apllication of the EP1 receptor inhibitor SC-51089 (1–100 μM) attenuated the increase in CBF induced by hypercapnia (Fig 1A)
Neither EP3 (L-798,106) nor EP4 receptor (ONO-AE3-208) inhibitor, affected these CBF responses (p>0.05; S1 and S2 Figs). In agreement with these pharmacological data, in EP1-/- mice the increase in CBF evoked by hypercapnia was attenuated (p0.05; Fig 2B)
Summary
Cerebral blood vessels are highly sensitive to changes in arterial partial pressure of carbon dioxide (pCO2). Even though many factors are likely involved in vasodilatation induced by hypercapnia [2,3,4], evidence suggests that prostanoids synthesized by cyclooxygenase (COX)-1 or -2 from arachidonic acid (AA) play a critical role in the hypercapnic response of the cerebral microcirculation. EP1 receptors in cerebral endothelial cells have been implicated in the cerebrovascular effects of hypertension [13, 14] It is unknown whether PGE2 acting on EP1 receptors play a role in the regulation of cerebrovascular response evoked by hypercapnia. We sought to determine whether COX-1-derived PGE2 and EP1 receptors are involved in the cerebrovascular response induced by hypercapnia. The findings highlight the critical role that COX-1 derived prostanoids and EP1 receptors play in the regulation of the cerebral circulation
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