Mechanism of the hypotensive action of anandamide in anesthetized rats.
We studied the effects of the endogenous cannabinoid ligand anandamide on blood pressure, single unit activity of barosensitive neurons in the rostral ventrolateral medulla, and postganglionic splanchnic sympathetic nerve discharge in urethane-anesthetized rats. In rats with an intact baroreflex, an intravenous bolus of 4 mg/kg anandamide caused a triphasic blood pressure response: transient hypotension, followed by a brief pressor and more prolonged depressor phase. Anandamide evoked a "primary" increase in neuronal firing coincident with its pressor effect and a "secondary," baroreflex-mediated rise coincident with its depressor effect at both sites. Pretreatment of rats with phentolamine or trimethaphan did not inhibit either the pressor response or the primary increase in splanchnic nerve discharge elicited by anandamide. In barodenervated rats, electrical stimulation of the rostral ventrolateral medulla increased blood pressure and splanchnic nerve discharge. Anandamide treatment blunted the rise in blood pressure without affecting the increase in splanchnic nerve discharge. Anandamide did not affect the rise in blood pressure in response to an intravenous bolus dose of phenylephrine. The results indicate that (1) the brief pressor response to anandamide is not sympathetically mediated, and (2) the prolonged hypotensive response to anandamide is not initiated in the central nervous system, in ganglia, or at postsynaptic adrenergic receptors but is due to a presynaptic action that inhibits norepinephrine release from sympathetic nerve terminals in the heart and vasculature.
Varga
K
K
Department of Pharmacology and Toxicology, Virginia, Commonwealth University, Medical College of Virginia, Richmond 23298, USA. kvarga@gems.vcu.edu
Lake
K D
KD
Huangfu
D
D
Guyenet
P G
PG
Kunos
G
G
D000758:Anesthesia; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002186:Cannabinoids / Q000494:pharmacology*; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D008297:Male; D053284:Polyunsaturated Alkamides; D011311:Pressoreceptors / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects
D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D013759:Dronabinol; C078814:anandamide