Endocannabinoid-mediated modulation of Gq/11 protein-coupled receptor signaling-induced vasoconstriction and hypertension

Szekeres, Mária; Nádasy, György L.; Turu, Gábor; Soltész‐Katona, Eszter; Benyó, Zoltán; Offermanns, Stefan; Ruisanchez, Éva; Szabó, Eszter; Takáts, Zoltán; Bátkai, Sándor; Tóth, Zsuzsanna; Hunyady, László

doi:10.1016/j.mce.2015.01.012

Cited by 31 publications

(55 citation statements)

References 42 publications

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“…It was observed that activation of the AT1 receptors by Ang II resulted in activation of CB 1 receptors via a DAGL‐dependent mechanism in Chinese hamster ovary (CHO) cells as well as in human embryonic kidney‐293 cells . Moreover, inhibition of DAGL in rat and mouse gracilis arteriole, mouse saphenous artery, rat and mouse aorta by tetrahydrolipstatin (THL) led to the enhancement of Ang II‐induced vasoconstriction (Table ). Another inhibitor of DAGL, RHC80267, did not modify the vasoconstrictor effect of Ang II in endothelium‐denuded, but did in endothelium‐intact, rPAs, confirming that rapid synthesis of 2‐AG, released from endothelial cells, plays a protective role against the AT1 receptor‐mediated vasoconstriction in these arteries .…”

Section: Angiotensin II and Endocannabinoidsmentioning

confidence: 99%

“…In rat, uterine arteries from the animal model that mimics many features of preeclampsia, a disorder characterized by the onset of hypertension, both FAAH and MAGL inhibitors (URB597 and JZL184, respectively), reduced the contractile response to Ang II, but in a CB 1 receptor‐independent manner . JZL184 attenuated the contraction responses evoked by Ang II in rPAs and rat and mouse aorta . AEA does not play a protective role against the AT 1 receptor‐mediated vasoconstriction in the pulmonary vascular bed, likely because URB597 does not modify the Ang II‐induced response in isolated rPAs (Table ) .…”

Section: Angiotensin II and Endocannabinoidsmentioning

confidence: 99%

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

Karpińska

Baranowska-Kuczko

Kloza

et al. 2017

Journal of Pharmacy and Pharmacology

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Section: Angiotensin II and Endocannabinoidsmentioning

confidence: 99%

Section: Angiotensin II and Endocannabinoidsmentioning

confidence: 99%

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

Karpińska

Baranowska-Kuczko

Kloza

et al. 2017

Journal of Pharmacy and Pharmacology

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“…Interestingly, α1-AR activation regulates each of these processes in the heart as well, suggesting that the EC system may participate broadly in the mechanisms underlying α1-mediated cardioprotection. Of particular significance to our current study, ECs have been shown to decrease responsiveness to AR agonist stimulation in the vasculature 58,59 , to mediate α1-induced glutamate neurotransmission in the central nervous system 60 , and to regulate peripheral norepinephrine release 61 . However, our study is the first to show an effect of α1-AR activation on EC biosynthesis.…”

Section: Discussionmentioning

confidence: 78%

The alpha-1A adrenergic receptor agonist A61603 reduces cardiac polyunsaturated fatty acid and endocannabinoid metabolites associated with inflammation in vivo

et al. 2016

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Introduction Alpha-1-adrenergic receptors (α1-ARs) are G-protein coupled receptors (GPCRs) with three highly homologous subtypes (α1A, α1B, and α1D). Of these three subtypes, only the α1A and α1B are expressed in the heart. Multiple pre-clinical models of heart injury demonstrate cardioprotective roles for the α1A. Non-selective α1-AR activation promotes glycolysis in the heart, but the functional α1-AR subtype and broader metabolic effects have not been studied. Objectives Given the high metabolic demands of the heart and previous evidence indicating benefit from α1A activation, we chose to investigate the effects of α1A activation on the cardiac metabolome in vivo. Methods Mice were treated for one week with a low, subpressor dose of A61603, a highly selective and potent α1A agonist. Cardiac tissue and serum were analyzed using a non-targeted metabolomics approach. Results We identified previously unrecognized metabolic responses to α1A activation, most notably broad reduction in the abundance of polyunsaturated fatty acids (PUFAs) and endocannabinoids (ECs). Conclusion Given the well characterized roles of PUFAs and ECs in inflammatory pathways, these findings suggest a possible role for cardiac α1A-ARs in the regulation of inflammation and may offer novel insight into the mechanisms underlying the cardioprotective benefit of selective pharmacologic α1A activation.

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“…Recently, 2-AG release by the vascular smooth muscle has been demonstrated as a consequence of the activation of certain seven-transmembrane domain receptors associated with heterotrimeric G q/11 proteins (223,224). In the process of intracellular signaling the G␣ q/11 subunit mediates activation of phospholipase C␤, which catalyzes the conversion of the cell membrane phospholipid phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate and diacylglycerol (DAG).…”

Section: Biosynthesis and Receptors Of Endocannabinoids In Cells Invomentioning

confidence: 99%

“…2, DAG can be further converted by DAG lipase to 2-AG, which can be released by the vascular smooth muscle cells and act as a paracrine mediator, reducing the tension of the vascular smooth muscle. This mechanism has been proposed as a negative feed-back control system for attenuating the vasoconstriction mediated by AT 1 angiotensin receptors and ␣ 1 -adrenoreceptors (223,224).…”

Section: Biosynthesis and Receptors Of Endocannabinoids In Cells Invomentioning

confidence: 99%

Endocannabinoids in cerebrovascular regulation

Benyó

Ruisanchez

Leszl-Ishiguro

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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The cerebral blood flow is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms under physiological conditions, and a large body of recent evidence indicates that inflammatory pathways have a major influence on the cerebral blood perfusion in certain central nervous system disorders, like hemorrhagic and ischemic stroke, traumatic brain injury, and vascular dementia. All major cell types involved in cerebrovascular control pathways (i.e., smooth muscle, endothelium, neurons, astrocytes, pericytes, microglia, and leukocytes) are capable of synthesizing endocannabinoids and/or express some or several of their target proteins [i.e., the cannabinoid 1 and 2 (CB1 and CB2) receptors and the transient receptor potential vanilloid type 1 ion channel]. Therefore, the endocannabinoid system may importantly modulate the regulation of cerebral circulation under physiological and pathophysiological conditions in a very complex manner. Experimental data accumulated since the late 1990s indicate that the direct effect of cannabinoids on cerebral vessels is vasodilation mediated, at least in part, by CB1 receptors. Cannabinoid-induced cerebrovascular relaxation involves both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium. However, under stress conditions (e.g., in conscious restrained animals or during hypoxia and hypercapnia), cannabinoid receptor activation was shown to induce a reduction of the cerebral blood flow, probably via inhibition of the electrical and/or metabolic activity of neurons. Finally, in certain cerebrovascular pathologies (e.g., subarachnoid hemorrhage, as well as traumatic and ischemic brain injury), activation of CB2 (and probably yet unidentified non-CB1/non-CB2) receptors appear to improve the blood perfusion of the brain via attenuating vascular inflammation. cerebral circulation; endocannabinoids; cannabinoid receptors; TRPV1 channel; neurovascular unit THE CEREBRAL VASCULATURE HAS two main homeostatic functions: 1) to adjust the local blood supply to the eventually rapidly changing metabolic demands of neurons; and 2) to maintain an optimal extracellular environment in the brain. The former function is realized by the regulation of the local cerebral blood flow (CBF), whereas the latter is achieved by the maintenance of the blood-brain barrier (BBB) and related transport mechanisms. The endocannabinoid system has been implicated as an important regulatory component in both of these cerebrovascular functions. The roles of endocannabinoids and cannabinoid receptors in the BBB have been reviewed recently (237). Here we aim to overview our knowledge on the endocannabinoid-mediated regulation of cerebral circulation.

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Endocannabinoid-mediated modulation of Gq/11 protein-coupled receptor signaling-induced vasoconstriction and hypertension

Cited by 31 publications

References 42 publications

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

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

The alpha-1A adrenergic receptor agonist A61603 reduces cardiac polyunsaturated fatty acid and endocannabinoid metabolites associated with inflammation in vivo

Endocannabinoids in cerebrovascular regulation

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