Abstract
BackgroundEndocannabinoids 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 FindingsIn 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/SignificanceUnder 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.
Highlights
Endocannabinoids (ECs) are endogenous bioactive lipid mediators exerting many of their effects in mammals through their specific G protein-coupled receptors [1]
In other in vivo observations in rats, both anandamide and the cannabinoid receptor 1 (CB1)-receptor agonist HU-210 elicited marked cerebral vasodilation, which was inhibited by a CB1-antagonist [32]. To address these contradictory findings and to clarify the role of ECs and CB1-receptors in cerebral circulation, we carried out experiments in rats with the administration of a CB1 receptor antagonist/inverse agonist (AM-251) and an EC reuptake inhibitor (AM-404) under resting physiological conditions and we examined the role of CB1-receptors in hypoxia and hypercapnia (H/H)
We show for the first time that while constitutive CB1 receptor activation appears to play a limited role in the maintenance of the resting cerebrocortical blood flow (CoBF), ECs modulate CoBF during H/H in a CB1-dependent manner, an interaction that may have a very important role in pathophysiological conditions associated with altered EC system
Summary
Endocannabinoids (ECs) are endogenous bioactive lipid mediators exerting many of their effects in mammals through their specific G protein-coupled receptors [1]. The main ECs are anandamide and 2-arachidonoyl glycerol (2-AG), the former favoring cannabinoid receptor 1 (CB1) and the latter, cannabinoid receptor 2 (CB2) [2]. These receptors are involved in mediating the effect of several constituent compounds of the plant Cannabis sativa (marijuana), such as D9-Tetrahydrocannabinol (D9-THC) and D9-Tetrahydrocannabivarin (D9-THCV) [3]. 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)
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