Perivascular expression and potent vasoconstrictor effect of dynorphin A in cerebral arteries.
BACKGROUND
Numerous 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.


RESULTS
Immunohistochemical 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 G(i/o)-protein mediated signaling by pertussis toxin. Finally, des-Tyr(1) 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.


CONCLUSIONS
DYN-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 G(i/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.
Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary. ruisanchez.eva@med.semmelweis-univ.hu
Éva
É
Ruisanchez
Attila
A
Cselenyák
Rege Sugárka
RS
Papp
Tamás
T
Németh
Krisztina
K
Káldi
Péter
P
Sándor
Zoltán
Z
Benyó
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D002536:Cerebral Arteries / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism*; D004399:Dynorphins / Q000378:metabolism* / Q000494:pharmacology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D008297:Male; D009412:Nerve Fibers / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000378:metabolism* / Q000494:pharmacology*
D017473:Receptors, Opioid, kappa; D014662:Vasoconstrictor Agents; D004399:Dynorphins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go