title: Obligatory Role of EP1 Receptors in the Increase in Cerebral Blood Flow Produced by Hypercapnia in the Mice.
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.
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America.
authors.forename: Ken
authors.initials: K
authors.lastname: Uekawa
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Koizumi
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brunier
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America.
authors.forename: Yorito
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America.
authors.forename: Laibaik
authors.identifier: http://orcid.org/0000-0001-7601-663X
authors.initials: L
authors.lastname: Park