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

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.

Changes in Cannabinoid Receptors, Aquaporin 4 and Vimentin Expression after Traumatic Brain Injury in Adolescent Male Mice. Association with Edema and Neurological Deficit

“…CB1 expression presented a negative correlation with brain edema. Since CB1 is located in the end-foot of astrocytes [ 52 ], which are the principal glial cells that control ion exchange [ 53 ] and modulate cerebral blood flow [ 54 ], a lower expression of CB1 could affect the ionic balance and may lead to altered brain edema formation and resolution. Moreover, previous studies [ 55 , 56 ] with endothelium derived from human brain capillaries and microvessels demonstrated that one of the endogenous agonists of CB1 receptor, 2-arachydonoil glycerol (2-AG), inhibits some of the effects of endothelin-1 (ET-1).…”

A Systematic Review of the Complex Effects of Cannabinoids on Cerebral and Peripheral Circulation in Animal Models

“…In isolated middle cerebral arteries of rats, the endogenous CB1 receptor-agonist 2-AG was shown to attenuate vasoconstriction by the thromboxane mimetic U-46619 (Hillard et al, 2007 ). More recently, Iring et al ( 2013 ) did not find any significant influence of CB1 receptor activity on the regulation of cerebrocortical circulation under resting conditions in normotensive rats when activating endogenous AEA. There was, however, an indication of CB1 receptor-independent systemic hypertension as a result to enhancement of endocannabinoids.…”

Endocannabinoids in cerebrovascular regulation

“…One may suppose, however, that the effects of exogenously applied phyto-or endocannabinoids may be quite different from those induced by a complex endogenous control system. To overcome these limitations, in a recent study, the effects of suppressed endocannabinoid activity on the regulation of the cerebrocortical blood flow was investigated (102). AM-251, which is both antagonist and inverse agonist of the CB1-receptors (87,178), failed to alter significantly either the systemic or the cerebral circulation.…”

“…The regulatory role of endocannabinoids in the systemic and cerebral circulation and the consequences of activating this system were investigated in an alternative way in a recent study (102). AM-404, a putative cannabinoid re-uptake inhibitor, which reportedly increases the endogenous levels of anandamide in the brain (64) induced triphasic changes in both the systemic and the cerebral circulation.…”