Obligatory Role of EP1 Receptors in the Increase in Cerebral Blood Flow Produced by Hypercapnia in the Mice

<div><p>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.</p></div

Obligatory Role of EP1 Receptors in the Increase in Cerebral Blood Flow Produced by Hypercapnia in the Mice - Fig 1

<p><b>Effect of the EP1 receptor inhibitor SC-51039 on the increase in CBF induced by hypercapnia (A), resting CBF (B), and on the increase in CBF induced by acetylcholine (C), A23187 (D), adenosine (E), or whisker stimulation (F) in wild-type mice</b>. LDU, laser-Doppler perfusion units; * p<0.05 from vehicle, analysis of variance and Tukey’s test; n = 5/group.</p

Cerebrovascular responses in EP1^-/- mice.

<p>A, increase in CBF produced by hypercapnia; B, CBF response produced by acetylcholine, A23187, adenosine, or whsiker stimulation. * p<0.05, paired t-test; n = 5/group.</p

EP1 receptor immunoreactivity in CD31-positive microvessels of the somatosensory cortex.

<p>EP1 receptor immunoreactivity (green) is colocalized with CD31⁺ cortical vessels (red, arrows) in EP1^+/+ (A), but barely detectible in EP1^-/- (B) mice. Scale bar, 100 μm.</p

CBF increases induced by AA or PGE₂.

<p>CBF increases induced by AA or PGE₂.</p