Cardiovascular effects of anandamide in anesthetized and conscious normotensive and hypertensive rats.
We previously showed that in anesthetized rats anandamide elicits bradycardia and a triphasic blood pressure response: transient hypotension secondary to a vagally mediated bradycardia, followed by a brief pressor and prolonged depressor response, the latter two effects being similar to those of delta 9-tetrahydrocannabinol (THC). The prolonged depressor but not the pressor response was reduced after alpha-adrenergic receptor blockade or cervical spinal cord transection and was inhibited by the cannabinoid type 1 (CB1) receptor antagonist SR141716A, suggesting CB1 receptor-mediated sympathoinhibition as the underlying mechanism. Here we examined the relationship between sympathetic tone and the cardiovascular effects of anandamide by testing these effects in both conscious and anesthetized, normotensive and spontaneously hypertensive rats. In urethane-anesthetized normotensive rats, SR141716A inhibited the prolonged depressor and bradycardic effects of anandamide and THC with similar potency, whereas it did not affect the pressor response to either agent. Anadamide caused similar hypotension in spontaneously breathing and in paralyzed, mechanically ventilated rats, suggesting that the hypotension is not secondary to respiratory effects. In conscious normotensive rats, anandamide elicited transient vagal activation and a brief pressor response, but the prolonged hypotensive component was absent. SR141716A potentiated and prolonged the brief pressor response to anandamide, suggesting that the depressor response may have been masked by an increased pressor response. All three phases of the anadamide response were present in both anesthetized and conscious spontaneously hypertensive rats, and the hypotensive component, inhibited by SR141716A in both, was more prolonged in the absence (> 50 minutes) than the presence (10 to 15 minutes) of anesthesia. We conclude that anandamide causes a non-CB1 receptor-mediated pressor and a CB1 receptor-mediated prolonged depressor response. The depressor response can be elicited in both conscious and anesthetized animals, but its magnitude depends on preexisting sympathetic tone.
Lake
K D
KD
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
Martin
B R
BR
Kunos
G
G
Varga
K
K
D000758:Anesthesia; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D006339:Heart Rate / Q000187:drug effects*; D006973:Hypertension / Q000503:physiopathology*; D007275:Injections, Intravenous; D008297:Male; D053284:Polyunsaturated Alkamides; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; C078814:anandamide