Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation

Iring, András

Ruisanchez, Éva

Leszl-Ishiguro, Miriam

Horváth, Béla András

Benkő, Rita

Lacza, Zsombor

Járai, Zoltán

Sándor, Péter

Di Marzo V

Pacher, Pál

Benyó, Zoltán

SE/ÁOK/I/Klinikai Kísérleti Kutató- és Humán Élettani Intézet

Semmelweis Egyetem

2014-03-25T13:22:42Z

2014-03-25T13:22:42Z

2013

2014-03-25T13:21:13Z

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). METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSION/SIGNIFICANCE: 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.

Journal Article

pagination=e53390, 11 pages; journalVolume=8; journalIssueNumber=1; journalTitle=PLOS ONE;

http://repo.lib.semmelweis.hu//handle/123456789/49

doi:10.1371/journal.pone.0053390

2181946

000313670100036

23308211

urn:issn:1932-6203