Perivascular Expression and Potent Vasoconstrictor Effect of Dynorphin A in Cerebral Arteries

Ruisanchez, Éva; Cselenyák, Attila; Papp, Rege Sugárka; Németh, Tamás; Káldi, Krisztina; Sándor, Péter; Benyó, Zoltán

doi:10.1371/journal.pone.0037798

Cited by 8 publications

(13 citation statements)

References 52 publications

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“…One obvious target is the cerebral vasculature itself, which appears to respond with vasodilation in a CB1-dependent manner [29], [30], [32]. On the other hand, cerebral circulation is tightly regulated by neuronal mechanisms [15], [16], [44], and in these pathways cannabinoids may act as modulators of the synaptic transmission. Finally, cannabinoids may have indirect effects on cerebral circulation by influencing the metabolic demand of neurons, or respiration and consequently blood gas tensions.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…Dynorphin is present in human cerebral perivascular nerves [94], which carry out similar roles to cerebrovascular functions. Dynorphin B, in particular, is expressed in human blood vessels [95].…”

Section: Modulatory Role For Dynorphins At the Level Of Central Nervousmentioning

confidence: 99%

“…Dyn 1-13 induces vasodilation via acting on the presynaptic neuronal NF-κB/p65 KOP [97]. Dynorphin A-mediated KOP activation sustains the contraction of rat cerebral arteries [94]. The KOP antagonist, nor-BNI [89], and G i/o antagonist, pertussis toxin, fail to completely abolish dynorphin-dependent vasoconstriction [94].…”

Section: Modulatory Role For Dynorphins At the Level Of Central Nervousmentioning

confidence: 99%

Dynorphins in Development and Disease: Implications for Cardiovascular Disease

Cissom

Paris

Shariat‐Madar

2020

CMM

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It is well-established that cardiovascular disease continues to represent a growing health problem and significant effort has been made to elucidate the underlying mechanisms. In this review, we report on past and recent high impact publications in the field of intracrine network signaling, focusing specifically on opioids and their interrelation with key modulators of the cardiovascular system and the onset of related disease. We present an overview of studies outlining the scope of cardiovascular and cerebrovascular processes that are affected by opioids, including heart function, ischemia, reperfusion, and blood flow. Specific emphasis is placed on the importance of dynorphin molecules in cerebrovascular and cardiovascular regulation. Evidence suggests that excessive or insufficient dynorphin could make an important contribution to cardiovascular physiology, yet numerous paradoxical observations frequently impede a clear understanding of the role of dynorphin. Thus, we argue that dynorphin-mediated signaling events for which an immediate regulatory effect is disputed should not be dismissed as unimportant, as they may play a role in cross-talk with other signaling networks. Finally, we consider the most recent evidence on the role of dynorphin during cardiovascular-related inflammation and on the potential value of endogenous and exogenous inhibitors of kappa-opioid receptor, a major dynorphin A receptor, to limit or prevent cardiovascular disease and its related sequelae.

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“…However, it became evident recently that neuronal mechanisms contribute significantly to the regulation of CBF, and, beside neurons and perivascular nerves, astrocytes are also active participants in these neurovascular control functions. It has been established for many decades that cerebral blood vessels receive innervation partly via the peripheral nervous system (autonomic and sensory fibers, including sympathetic and parasympathetic nerves, originating in the superior cervical, sphenopalatine, otic, and trigeminal ganglia) and partly within the CNS (from the locus coeruleus, basal nucleus of Meynert, dorsal raphe nuclei, and fastigial nucleus) (18,62,101,199). However, the functional significance of this dense innervation was unclear for a long time, partly because of the marked diversity of experimental observations obtained in different species, under different types of anesthesia and in different brain regions (202).…”

Section: Regulatory Mechanisms Of the Cerebral Circulationmentioning

confidence: 99%

“…The cerebral circulation is tightly regulated by neuronal mechanisms (86,199,202), in which endocannabinoids may act as modulators of synaptic transmission (Fig. 3) and, thereby, influence the activity of neuronal pathways.…”

Section: Cerebrovascular Actions Of Exogenous and Endogenous Cannabinmentioning

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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Perivascular Expression and Potent Vasoconstrictor Effect of Dynorphin A in Cerebral Arteries

Cited by 8 publications

References 52 publications

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

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

Dynorphins in Development and Disease: Implications for Cardiovascular Disease

Endocannabinoids in cerebrovascular regulation

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