Abstract
BackgroundNumerous literary data indicate that dynorphin A (DYN-A) has a significant impact on cerebral circulation, especially under pathophysiological conditions, but its potential direct influence on the tone of cerebral vessels is obscure. The aim of the present study was threefold: 1) to clarify if DYN-A is present in cerebral vessels, 2) to determine if it exerts any direct effect on cerebrovascular tone, and if so, 3) to analyze the role of κ-opiate receptors in mediating the effect.Methodology/Principal FindingsImmunohistochemical analysis revealed the expression of DYN-A in perivascular nerves of rat pial arteries as well as in both rat and human intraparenchymal vessels of the cerebral cortex. In isolated rat basilar and middle cerebral arteries (BAs and MCAs) DYN-A (1–13) and DYN-A (1–17) but not DYN-A (1–8) or dynorphin B (DYN-B) induced strong vasoconstriction in micromolar concentrations. The maximal effects, compared to a reference contraction induced by 124 mM K+, were 115±6% and 104±10% in BAs and 113±3% and 125±9% in MCAs for 10 µM of DYN-A (1–13) and DYN-A (1–17), respectively. The vasoconstrictor effects of DYN-A (1–13) could be inhibited but not abolished by both the κ-opiate receptor antagonist nor-Binaltorphimine dihydrochloride (NORBI) and blockade of Gi/o-protein mediated signaling by pertussis toxin. Finally, des-Tyr1 DYN-A (2–13), which reportedly fails to activate κ-opiate receptors, induced vasoconstriction of 45±11% in BAs and 50±5% in MCAs at 10 µM, which effects were resistant to NORBI.Conclusion/SignificanceDYN-A is present in rat and human cerebral perivascular nerves and induces sustained contraction of rat cerebral arteries. This vasoconstrictor effect is only partly mediated by κ-opiate receptors and heterotrimeric Gi/o-proteins. To our knowledge our present findings are the first to indicate that DYN-A has a direct cerebral vasoconstrictor effect and that a dynorphin-induced vascular action may be, at least in part, independent of κ-opiate receptors.
Highlights
The perivascular nerves of brain vessels were already recognized by Thomas Willis in the 17th century [1], their role in the regulation of cerebral circulation is still poorly understood [2,3]
Since we found that dynorphin A (DYN-A) is present in perivascular nerves of cerebral arteries and induces sustained vasoconstriction, we further investigated the roles of k-opiate receptors and Gi/o proteins in mediating this vasoactive effect
In a review published in 1996, based on the literature available at the time, we drew the conclusion that the endogenous opioid system represents a latent regulatory mechanism, which is of limited importance under resting conditions but may significantly influence cerebral circulation in pathophysiological states [8]
Summary
The perivascular nerves of brain vessels were already recognized by Thomas Willis in the 17th century [1], their role in the regulation of cerebral circulation is still poorly understood [2,3]. Since the development of the metabolic homeostasis concept by Roy and Sherrington in 1890 [4], cerebrovascular research has been focused primarily on paracrine mediators of cerebral blood flow (CBF) regulation. In some disorders of the cerebral circulation, like vascular migraine headache, vasomotion and vasospasm following subarachnoid hemorrhage or traumatic brain injury, CBF is completely uncoupled from the metabolic demands of neurons. The aim of the present study was threefold: 1) to clarify if DYN-A is present in cerebral vessels, 2) to determine if it exerts any direct effect on cerebrovascular tone, and if so, 3) to analyze the role of k-opiate receptors in mediating the effect
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
