title: Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation.
abstract: BACKGROUND
  Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1) receptor blockade and inhibition of cannabinoid reuptake, respectively) on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H).
  
  
  RESULTS
  In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v.) failed to influence blood pressure (BP), cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry) or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v.) induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H.
  
  
  CONCLUSIONS
  Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the first time the involvement of the endocannabinoid system and CB1-receptors in the regulation of the cerebral circulation during H/H and also raise the possibility of their contribution to the autoregulation of CoBF.
authors: Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary.
authors: András
authors: A
authors: Iring
authors: Éva
authors: É
authors: Ruisanchez
authors: Miriam
authors: M
authors: Leszl-Ishiguro
authors: Béla
authors: B
authors: Horváth
authors: Rita
authors: R
authors: Benkő
authors: Zsombor
authors: Z
authors: Lacza
authors: Zoltán
authors: Z
authors: Járai
authors: Péter
authors: P
authors: Sándor
authors: Vincenzo
authors: V
authors: Di Marzo
authors: Pál
authors: P
authors: Pacher
authors: Zoltán
authors: Z
authors: Benyó
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D062186:Arterial Pressure / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D063388:Endocannabinoids / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006935:Hypercapnia / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C107594:N-(4-hydroxyphenyl)arachidonylamide