Cannabinoid and lipid-mediated vasorelaxation in retinal microvasculature

Jessica Macintyre; Alex Dong; Alex Straiker; Jiequan Zhu; Susan E. Howlett; Amina Bagher; Eileen Denovan-Wright; Dao Yi Yu; Melanie E.M. Kelly

doi:10.1016/j.ejphar.2014.03.055

Cannabinoid and lipid-mediated vasorelaxation in retinal microvasculature

Jessica Macintyre, Alex Dong, Alex Straiker, Jiequan Zhu, Susan E. Howlett, Amina Bagher, Eileen Denovan-Wright, Dao Yi Yu, Melanie E.M. Kelly

Medicine

Research output: Contribution to journal › Article › peer-review

51 Citations (Scopus)

Abstract

The endocannabinoid system plays a role in regulation of vasoactivity in the peripheral vasculature; however, little is known about its role in regulation of the CNS microvasculature. This study investigated the pharmacology of cannabinoids and cannabimimetic lipids in the retinal microvasculature, a CNS vascular bed that is autoregulated. Vessel diameter (edge detector) and calcium transients (fura-2) were recorded from segments of retinal microvasculature isolated from adult, male Fischer 344 rats. Results showed that abnormal cannabidiol (Abn-CBD), an agonist at the putative endothelial cannabinoid receptor, CB_e, inhibited endothelin 1 (ET-1) induced vasoconstriction in retinal arterioles. These actions of Abn-CBD were independent of CB₁/CB₂ receptors and were not mediated by agonists for GPR55 or affected by nitric oxide synthase (NOS) inhibition. However, the vasorelaxant effects of Abn-CBD were abolished when the endothelium was removed and were inhibited by the small Ca²⁺-sensitive K channel (SK_Ca) blocker, apamin. The effects of the endogenous endocannabinoid metabolite, N-arachidonyl glycine (NAGly), a putative agonist for GPR18, were virtually identical to those of Abn-CBD. GPR18 mRNA and protein were present in the retina, and immunohistochemistry demonstrated that GPR18 was localized to the endothelium of retinal vessels. These findings demonstrate that Abn-CBD and NAGly inhibit ET-1 induced vasoconstriction in retinal arterioles by an endothelium-dependent signaling mechanism that involves SK _Ca channels. The endothelial localization of GPR18 suggests that GPR18 could contribute to cannabinoid and lipid-mediated retinal vasoactivity.

Original language	English
Pages (from-to)	105-114
Number of pages	10
Journal	European Journal of Pharmacology
Volume	735
Issue number	1
DOIs	https://doi.org/10.1016/j.ejphar.2014.03.055
Publication status	Published - Jul 15 2014

Bibliographical note

Funding Information:
This study was supported by operating grants from the Canadian Institutes of Health Research to MEMK ( MOP-97768 ) and SEH ( MOP-97973 ), and the National Science and Engineering Research Council to MEMK . The authors are grateful to Dr. Heather Bradshaw for the provision of necessary reagents for the PCR experiments and valuable comments on this work, as well as to Elizabeth Cairns and Peter Nicholl for editorial and technical assistance.

ASJC Scopus Subject Areas

Pharmacology

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10.1016/j.ejphar.2014.03.055

Cite this

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title = "Cannabinoid and lipid-mediated vasorelaxation in retinal microvasculature",

abstract = "The endocannabinoid system plays a role in regulation of vasoactivity in the peripheral vasculature; however, little is known about its role in regulation of the CNS microvasculature. This study investigated the pharmacology of cannabinoids and cannabimimetic lipids in the retinal microvasculature, a CNS vascular bed that is autoregulated. Vessel diameter (edge detector) and calcium transients (fura-2) were recorded from segments of retinal microvasculature isolated from adult, male Fischer 344 rats. Results showed that abnormal cannabidiol (Abn-CBD), an agonist at the putative endothelial cannabinoid receptor, CBe, inhibited endothelin 1 (ET-1) induced vasoconstriction in retinal arterioles. These actions of Abn-CBD were independent of CB1/CB2 receptors and were not mediated by agonists for GPR55 or affected by nitric oxide synthase (NOS) inhibition. However, the vasorelaxant effects of Abn-CBD were abolished when the endothelium was removed and were inhibited by the small Ca2+-sensitive K channel (SKCa) blocker, apamin. The effects of the endogenous endocannabinoid metabolite, N-arachidonyl glycine (NAGly), a putative agonist for GPR18, were virtually identical to those of Abn-CBD. GPR18 mRNA and protein were present in the retina, and immunohistochemistry demonstrated that GPR18 was localized to the endothelium of retinal vessels. These findings demonstrate that Abn-CBD and NAGly inhibit ET-1 induced vasoconstriction in retinal arterioles by an endothelium-dependent signaling mechanism that involves SK Ca channels. The endothelial localization of GPR18 suggests that GPR18 could contribute to cannabinoid and lipid-mediated retinal vasoactivity.",

author = "Jessica Macintyre and Alex Dong and Alex Straiker and Jiequan Zhu and Howlett, {Susan E.} and Amina Bagher and Eileen Denovan-Wright and Yu, {Dao Yi} and Kelly, {Melanie E.M.}",

note = "Funding Information: This study was supported by operating grants from the Canadian Institutes of Health Research to MEMK ( MOP-97768 ) and SEH ( MOP-97973 ), and the National Science and Engineering Research Council to MEMK . The authors are grateful to Dr. Heather Bradshaw for the provision of necessary reagents for the PCR experiments and valuable comments on this work, as well as to Elizabeth Cairns and Peter Nicholl for editorial and technical assistance. ",

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AU - Yu, Dao Yi

AU - Kelly, Melanie E.M.

N1 - Funding Information: This study was supported by operating grants from the Canadian Institutes of Health Research to MEMK ( MOP-97768 ) and SEH ( MOP-97973 ), and the National Science and Engineering Research Council to MEMK . The authors are grateful to Dr. Heather Bradshaw for the provision of necessary reagents for the PCR experiments and valuable comments on this work, as well as to Elizabeth Cairns and Peter Nicholl for editorial and technical assistance.

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N2 - The endocannabinoid system plays a role in regulation of vasoactivity in the peripheral vasculature; however, little is known about its role in regulation of the CNS microvasculature. This study investigated the pharmacology of cannabinoids and cannabimimetic lipids in the retinal microvasculature, a CNS vascular bed that is autoregulated. Vessel diameter (edge detector) and calcium transients (fura-2) were recorded from segments of retinal microvasculature isolated from adult, male Fischer 344 rats. Results showed that abnormal cannabidiol (Abn-CBD), an agonist at the putative endothelial cannabinoid receptor, CBe, inhibited endothelin 1 (ET-1) induced vasoconstriction in retinal arterioles. These actions of Abn-CBD were independent of CB1/CB2 receptors and were not mediated by agonists for GPR55 or affected by nitric oxide synthase (NOS) inhibition. However, the vasorelaxant effects of Abn-CBD were abolished when the endothelium was removed and were inhibited by the small Ca2+-sensitive K channel (SKCa) blocker, apamin. The effects of the endogenous endocannabinoid metabolite, N-arachidonyl glycine (NAGly), a putative agonist for GPR18, were virtually identical to those of Abn-CBD. GPR18 mRNA and protein were present in the retina, and immunohistochemistry demonstrated that GPR18 was localized to the endothelium of retinal vessels. These findings demonstrate that Abn-CBD and NAGly inhibit ET-1 induced vasoconstriction in retinal arterioles by an endothelium-dependent signaling mechanism that involves SK Ca channels. The endothelial localization of GPR18 suggests that GPR18 could contribute to cannabinoid and lipid-mediated retinal vasoactivity.

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Cannabinoid and lipid-mediated vasorelaxation in retinal microvasculature

Abstract

Bibliographical note

ASJC Scopus Subject Areas

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