Role of Endocannabinoids and Cannabinoid-1 Receptors in Cerebrocortical Blood Flow Regulation

András Iring, Éva Ruisanchez, Miriam Leszl-Ishiguro, Béla Horváth, Rita Benko, Zsombor Lacza, Zoltán Járai, Péter Sándor, Vincenzo Di Marzo, Pál Pacher, Zoltán Benyó

Research output: Article

11 Citations (Scopus)

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). 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.

Original languageEnglish
Article numbere53390
JournalPloS one
Volume8
Issue number1
DOIs
Publication statusPublished - jan. 4 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Iring, A., Ruisanchez, É., Leszl-Ishiguro, M., Horváth, B., Benko, R., Lacza, Z., Járai, Z., Sándor, P., Di Marzo, V., Pacher, P., & Benyó, Z. (2013). Role of Endocannabinoids and Cannabinoid-1 Receptors in Cerebrocortical Blood Flow Regulation. PloS one, 8(1), [e53390]. https://doi.org/10.1371/journal.pone.0053390