Abstract
This study was designed to investigate the vasorelaxant effects and underlying mechanism of isocorynoxeine (ICN), one of the indole alkaloids from Uncaria hooks, on isolated mesenteric arteries in vitro. The myograph system was applied for isometric tension recording in the vascular rings. ICN relaxed both endothelium-intact and endothelium-denuded rat vascular rings precontracted with phenylephrine or KCl in a dose-dependent manner. Propranolol, tetraethylammonium, BaCl2, and glibenclamide had no influence on the vasodilator effect of ICN on phenylephrine-primed vascular rings, while 4-aminopyridine decreased the maximum relaxation. Furthermore, ICN produced a significant drop in maximum response in the PE log concentration-response curve without shifting to the right. In the Ca2+-free Kreb’s-Henseleit buffer, ICN inhibited the contraction in vascular rings evoked by PE, but not by KCl. The phasic contractions of segments in the Ca2+-free Kreb’s-Henseleit buffer induced by CaCl2 were restrained by ICN, while contractions elicited by caffeine displayed no differences. Furthermore, the phasic vasodilation of ICN was significantly lower than controls when pretreated with nifedipine and heparin. Both BAYK8644- and PE-evoked responses were significantly inhibited in the presence of 100 μM of ICN in human vascular smooth muscle cells loaded with the fluorescent Ca2+ indicator Fluo-4-AM. All these results suggest that ICN act in an endothelium-independent manner on the mesenteric artery. Its mechanisms of vasorelaxant action were produced by the inhibition of L-type calcium channel-mediated external Ca2+ influx and α1A-adrenoceptor-mediated intracellular Ca2+ release in vascular smooth muscle cells, and the participation of the Kv channel.
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Acknowledgements
We gratefully acknowledge the National Natural Science Foundation of China (No. 81673398) for financial support.
Author contribution statement
SW and TL conceived of or designed study. TL and KX performed research. TL and NJ analyzed data. ZH and DC contributed new reagents and analytical tools. TL wrote the paper. All authors read and approved the manuscript.
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This study was funded by National Natural Science Foundation of China (No. 81673398).
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All procedures performed in studies involving animals were in accordance with the ethical standards of the Ethical Committee of Xi’an Jiaotong University.
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Supplementary Fig 7
The LC/MS-IT-TOF MS spectra of ICN (GIF 8 kb)
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Li, T., Xu, K., Che, D. et al. Endothelium-independent vasodilator effect of isocorynoxeine in vitro isolated from the hook of Uncaria rhynchophylla (Miquel). Naunyn-Schmiedeberg's Arch Pharmacol 391, 1285–1293 (2018). https://doi.org/10.1007/s00210-018-1536-y
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DOI: https://doi.org/10.1007/s00210-018-1536-y