Factors influencing the regional haemodynamic responses to methanandamide and anandamide in conscious rats.
OBJECTIVE
In vitro evidence suggests that metabolism of anandamide by cyclooxygenase-2 (COX-2) may be more important when the primary metabolic pathway [i.e. fatty acid amide hydrolase (FAAH)] is inhibited. Thus, the first aim of the present study was to assess the effects of COX-2 and/or FAAH inhibition, on the cardiovascular actions of anandamide. The second aim was to compare the effects of anandamide with those of the metabolically stable analogue (i.e. methanandamide) and investigate mechanisms involved in responses to the latter in conscious rats.


METHODS
Rats were chronically instrumented for recording blood pressure, heart rate and renal, mesenteric and hindquarters vascular conductances in the freely moving state.


RESULTS
Inhibition of FAAH with URB597 (cyclohexycarbamic acid 3'-carbamoyl-biphenyl-3-yl-ester) augmented the haemodynamic actions of anandamide, but there was no effect of COX-2 inhibition with parecoxib, either in the absence or the presence of URB597. Methanandamide caused CB(1) receptor-mediated renal and mesenteric vasoconstriction and evoked beta(2)-adrenoceptor-mediated hindquarters vasodilatation.


CONCLUSIONS
No evidence for an involvement of COX-2 in the systemic cardiovascular actions of anandamide could be demonstrated. Vasoconstrictor actions of methanandamide were shown to involve CB(1) receptors, whereas no involvement of CB(1) receptors in such actions of anandamide has been shown. However, beta(2)-adrenoceptor-mediated hindquarters vasodilatation, independent of CB(1) receptors, observed here with methanandamide, has previously been seen with anandamide and differs from previous results with other synthetic cannabinoids for which the response was CB(1) receptor-dependent. Thus, mechanisms underlying the cardiovascular actions of endocannabinoids and synthetic analogues appear to be agonist-specific.
Gardiner
S M
SM
Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham, Nottingham, UK. sheila.gardiner@nottingham.ac.uk
March
J E
JE
Kemp
P A
PA
Bennett
T
T
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003243:Consciousness; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D063388:Endocannabinoids; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D008297:Male; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects
D001095:Arachidonic Acids; D004338:Drug Combinations; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; C088155:methanandamide; C078814:anandamide
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