Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin.
Anandamide (AN, arachidonyl ethanolamide) has been isolated from the brain and shown to be an endogenous ligand for the delta 9-tetrahydrocannabinol (delta 9-THC) receptor. The purpose of these studies was to determine whether AN or delta 9-THC can affect the cerebral circulation. With the use of the closed cranial window AN and delta 9-THC (10(-13)-10(-3) M) were topically applied to rabbit cerebral arterioles and effects on diameter were measured with a microscope. AN and delta 9-THC similarly induced a dose-dependent dilation starting at concentrations as low as 10(-12) M. Maximum dilation for AN was 25% and that for delta 9-THC 22%. Topical coapplication of indomethacin, a cyclooxygenase inhibitor, completely blocked dilation, whereas the free radical scavengers superoxide dismutase and catalase or the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) had no effect on AN-induced dilation. The cerebrospinal fluid level of prostaglandin E2 increased only in response to 10(-7) M and greater AN and was not affected by delta 9-THC. [3H]AN superfused through the cranial window was 20% converted to arachidonic acid. These results show that AN and delta 9-THC can modulate cerebral arterioles, likely by stimulating release and metabolism of endogenous arachidonic acid. Whether dilation is due to vasodilator eicosanoids, or other vasoactive agents whose synthesis or release is cyclooxygenase dependent, is uncertain.
Ellis
E F
EF
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
Moore
S F
SF
Willoughby
K A
KA
D000287:Administration, Topical; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001160:Arterioles / Q000187:drug effects; D002186:Cannabinoids / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000134:cerebrospinal fluid; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D063388:Endocannabinoids; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D053284:Polyunsaturated Alkamides; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects*
D001095:Arachidonic Acids; D002186:Cannabinoids; D016861:Cyclooxygenase Inhibitors; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D013759:Dronabinol; D015232:Dinoprostone; C078814:anandamide; D007213:Indomethacin