Endocannabinoids modulate Gq/11 protein-coupled receptor agonist-induced vasoconstriction via a negative feedback mechanism

Abstract

Endocannabinoid's negative feedback is responsible for diminishing agonist-induced vasoconstriction, which may be clinically important in the treatment of arterial and pulmonary hypertension. Further research is required to establish the importance of the eCB system and its downstream signalling pathways.

Beneficial Changes in Rat Vascular Endocannabinoid System in Primary Hypertension and under Treatment with Chronic Inhibition of Fatty Acid Amide Hydrolase by URB597

“…These results revealed that the contractions induced by the above agents were diminished by the CB 1 -dependent vasodilatory effects of endocannabinoids. They are following the previous suggestion that the production of endocannabinoids in the vasculature and, therefore, the degree of inhibition of vessel contraction may be dependent on agonist-induced contraction force ([ 19 ]; in our hands, U46619 is a more potent vasoconstrictor than phenylephrine). This novel CB 1 -dependent negative feedback mechanism, which restrains the increase in vascular tone, has mainly been described under in vitro conditions (for literature, see the Introduction, Figure 1 ).…”

“…Chronic URB597 increased vascular anandamide levels but did not modify the local protective feedback we observed in mesenteric G3 arteries isolated from hyper- and normotensive rats, which led to a decrease in vasoconstriction elicited by phenylephrine and U46619 by endocannabinoids acting through CB 1 receptors. However, it has been previously determined that this mechanism is not sensitive to FAAH but is enhanced only by MAGL inhibitors in human and rat pulmonary arteries [ 18 ] or in rat middle cerebral arteries [ 17 ], demonstrating the involvement of 2-AG, but not AEA in this effect (as reviewed by [ 19 ]). In our study, URB597 increased 2-AG content in aortas only, in which this negative feedback was not present.…”

“…The question arises whether URB597 would be an effective hypotensive if we used female SHR instead of males, as, in SHR, the response to anandamide in mesenteric G3 arteries was decreased in hypertensive males but not changed in female rats. We determined that the CB 1 receptor-dependent vascular feedback protecting against vasoconstrictor compounds involves 2-AG rather than anandamide [ 18 , 19 ]. As such, it would be interesting to examine the vascular effects of the chronic administration of a MAGL inhibitor or dual FAAH/MAGL inhibitor in hypertension.…”

“…(4) The upregulation of CB 1 receptors at the protein and/or gene level has been noted in rat mesenteric G3 arteries in DOCA-salt [ 4 ] and SHR [ 5 ] and in the aortic endothelium of SHR [ 6 ] and 2K1C [ 13 ]. (5) Protective CB 1 receptor-mediated vasorelaxation is induced by endocannabinoids released upon stimulation by various vasoconstrictors (e.g., an analog of thromboxane A 2 , U46619; phenylephrine; and angiotensin II) in the systemic (i.e., aortas, cerebral, resistance gracilis, and coronary arteries; [ 14 , 15 , 16 , 17 ]) and pulmonary circulations [ 18 , 19 ] ( Figure 1 ). FAAH inhibitors have been suggested as a promising target for antihypertensive drugs, as they enhance endocannabinoid signaling [ 1 , 2 ].…”

Cannabinoids—A New Perspective in Adjuvant Therapy for Pulmonary Hypertension

“…As mentioned above, the ECS is located in the pulmonary circulation (for reviews, see Kicman and Toczek [ 29 ] and Karpińska et al [ 48 ]) ( Table 1 ), and its endocannabinoid components can cause the relaxation of systemic vessels, resulting in a decrease in BP [ 12 ]. Therefore, the question emerges as to whether these components could also have hypotensive effects in the pulmonary circulation.…”