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Research ArticleCardiovascular

Endothelium-Dependent Contractions of Isolated Arteries to Thymoquinone Require Biased Activity of Soluble Guanylyl Cyclase with Subsequent Cyclic IMP Production

Charlotte M. Detremmerie, Zhengju Chen, Zhuoming Li, Khalid M. Alkharfy, Susan W.S. Leung, Aimin Xu, Yuansheng Gao and Paul M. Vanhoutte
Journal of Pharmacology and Experimental Therapeutics September 2016, 358 (3) 558-568; DOI: https://doi.org/10.1124/jpet.116.234153
Charlotte M. Detremmerie
Department of Pharmacology and Pharmacy and State Key Laboratory for Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong S.A.R., China (C.M.D., Z.L., S.W.S.L., A.X., P.M.V.); Department of Clinical Pharmacy, King Saud University, Saudi Arabia (K.M.A.) and Department of Physiology and Pathophysiology, Peking University Health Science Centre, Beijing, China (Z.C., Y.G.)
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Zhengju Chen
Department of Pharmacology and Pharmacy and State Key Laboratory for Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong S.A.R., China (C.M.D., Z.L., S.W.S.L., A.X., P.M.V.); Department of Clinical Pharmacy, King Saud University, Saudi Arabia (K.M.A.) and Department of Physiology and Pathophysiology, Peking University Health Science Centre, Beijing, China (Z.C., Y.G.)
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Zhuoming Li
Department of Pharmacology and Pharmacy and State Key Laboratory for Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong S.A.R., China (C.M.D., Z.L., S.W.S.L., A.X., P.M.V.); Department of Clinical Pharmacy, King Saud University, Saudi Arabia (K.M.A.) and Department of Physiology and Pathophysiology, Peking University Health Science Centre, Beijing, China (Z.C., Y.G.)
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Khalid M. Alkharfy
Department of Pharmacology and Pharmacy and State Key Laboratory for Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong S.A.R., China (C.M.D., Z.L., S.W.S.L., A.X., P.M.V.); Department of Clinical Pharmacy, King Saud University, Saudi Arabia (K.M.A.) and Department of Physiology and Pathophysiology, Peking University Health Science Centre, Beijing, China (Z.C., Y.G.)
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Susan W.S. Leung
Department of Pharmacology and Pharmacy and State Key Laboratory for Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong S.A.R., China (C.M.D., Z.L., S.W.S.L., A.X., P.M.V.); Department of Clinical Pharmacy, King Saud University, Saudi Arabia (K.M.A.) and Department of Physiology and Pathophysiology, Peking University Health Science Centre, Beijing, China (Z.C., Y.G.)
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Aimin Xu
Department of Pharmacology and Pharmacy and State Key Laboratory for Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong S.A.R., China (C.M.D., Z.L., S.W.S.L., A.X., P.M.V.); Department of Clinical Pharmacy, King Saud University, Saudi Arabia (K.M.A.) and Department of Physiology and Pathophysiology, Peking University Health Science Centre, Beijing, China (Z.C., Y.G.)
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Yuansheng Gao
Department of Pharmacology and Pharmacy and State Key Laboratory for Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong S.A.R., China (C.M.D., Z.L., S.W.S.L., A.X., P.M.V.); Department of Clinical Pharmacy, King Saud University, Saudi Arabia (K.M.A.) and Department of Physiology and Pathophysiology, Peking University Health Science Centre, Beijing, China (Z.C., Y.G.)
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Paul M. Vanhoutte
Department of Pharmacology and Pharmacy and State Key Laboratory for Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong S.A.R., China (C.M.D., Z.L., S.W.S.L., A.X., P.M.V.); Department of Clinical Pharmacy, King Saud University, Saudi Arabia (K.M.A.) and Department of Physiology and Pathophysiology, Peking University Health Science Centre, Beijing, China (Z.C., Y.G.)
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Abstract

Preliminary experiments on isolated rat arteries demonstrated that thymoquinone, a compound widely used for its antioxidant properties and believed to facilitate endothelium-dependent relaxations, as a matter of fact caused endothelium-dependent contractions. The present experiments were designed to determine the mechanisms underlying this unexpected response. Isometric tension was measured in rings (with and without endothelium) of rat mesenteric arteries and aortae and of porcine coronary arteries. Precontracted preparations were exposed to increasing concentrations of thymoquinone, which caused concentration-dependent, sustained further increases in tension (augmentations) that were prevented by endothelium removal, Nω-nitro-L-arginine methyl ester [L-NAME; nitric oxide (NO) synthase inhibitor], and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; soluble guanylyl cyclase [sGC] inhibitor). In L-NAME–treated rings, the NO-donor diethylenetriamine NONOate restored the thymoquinone-induced augmentations; 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol (sGC activator) and cyclic IMP (cIMP) caused similar restorations. By contrast, in ODQ-treated preparations, the cell-permeable cGMP analog did not restore the augmentation by thymoquinone. The compound augmented the content (measured with ultra-high performance liquid chromatography–tandem mass spectrometry) of cIMP, but not that of cGMP; these increases in cIMP content were prevented by endothelium removal, L-NAME, and ODQ. The augmentation of contractions caused by thymoquinone was prevented in porcine arteries, but not in rat arteries, by 1-(5-isoquinolinylsulfonyl)homopiperazine dihydrochloride and trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide dihydrochloride (Rho-kinase inhibitors); in the latter, but not in the former, it was reduced by 3,5-dichloro-N-[[(1α,5α,6-exo,6α)-3-(3,3-dimethylbutyl)-3-azabicyclo[3.1.0]hex-6-yl]methyl]-benzamide hydrochloride (T-type calcium channel inhibitor), demonstrating species/vascular bed differences in the impact of cIMP on calcium handling. Thymoquinone is the first pharmacological agent that causes endothelium-dependent augmentation of contractions of isolated arteries, which requires endothelium-derived NO and biased sGC activation, resulting in the augmented production of cIMP favoring the contractile process.

Footnotes

    • Received April 2, 2016.
    • Accepted June 15, 2016.
  • ↵1 Current affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.

  • This work was supported in part by the Distinguished Scientific Fellowship Program of King Saud University (Riyadh, Saudi Arabia) and by the General Research Fund [17112914] of the Hong Kong Research Grant Council.

  • dx.doi.org/10.1124./jpet.116.234153.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 358 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 358, Issue 3
1 Sep 2016
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Research ArticleCardiovascular

Vasoconstrictions Requiring Biased Activity of sGC

Charlotte M. Detremmerie, Zhengju Chen, Zhuoming Li, Khalid M. Alkharfy, Susan W.S. Leung, Aimin Xu, Yuansheng Gao and Paul M. Vanhoutte
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 558-568; DOI: https://doi.org/10.1124/jpet.116.234153

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Research ArticleCardiovascular

Vasoconstrictions Requiring Biased Activity of sGC

Charlotte M. Detremmerie, Zhengju Chen, Zhuoming Li, Khalid M. Alkharfy, Susan W.S. Leung, Aimin Xu, Yuansheng Gao and Paul M. Vanhoutte
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 558-568; DOI: https://doi.org/10.1124/jpet.116.234153
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