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Conference Paper: Biased activation of soluble Guanylyl Cyclase can cause contraction of isolated arteries

TitleBiased activation of soluble Guanylyl Cyclase can cause contraction of isolated arteries
Authors
Issue Date2016
PublisherFederation of American Societies for Experimental Biology. The Journal's web site is located at http://www.fasebj.org/
Citation
The 2016 Annual Meeting of the American Society of Pharmacology and Experimental (ASPET) held in conjunction with the Experimental Biology 2016 (EB 2016) Meeting, San Diego, CA., 2-6 April 2016. In The FASEB Journal, 2016, v. 30 Meeting Abstracts, no. 719.11 How to Cite?
AbstractOBJECTIVE To identify the mechanisms underlying the unexpected augmentation of contraction caused by thymoquinone, a natural compound with vasodilator properties, in isolated arteries. METHODS Ex vivo experiments were conducted in isolated mesenteric arteries and aortae of twelve to fourteen weeks old Sprague-Dawley rats and in porcine coronary arteries. The arteries were cut into rings (with or without endothelium) and suspended in organ chambers for isometric tension measurement in the absence and presence of pharmacological inhibitors. Following the establishment of an optimal basal tension, the preparations were contracted with phenylephrine (rat arteries) or serotonin (porcine arteries) and exposed to thymoquinone (10−7 to 10−3 M). Some rings were pooled for Western blotting of phosphorylated endothelial nitric oxide synthase (eNOS) and total eNOS or for the measurement of cyclic nucleotides levels with ultra-high performance liquid chromatography coupled with tandem mass spectrometry detection (UPLC-MS/MS). RESULTS In the three different arteries, thymoquinone caused a further concentration-dependent contraction, which was prevented by endothelium-removal. The augmentation of contraction was not significantly affected by anti-oxidants or by inhibitors of cyclooxygenases or endothelin-receptors. While Western blotting demonstrated increased phosphorylation of eNOS with thymoquinone, the augmentation was prevented by L-NAME [nitric oxide (NO) synthase inhibitor] and ODQ [soluble guanylyl cyclase (sGC) inhibitor]. In L-NAME-treated rings, the NO-donor diethylenetriamine NONOate restored or even increased thymoquinone-induced contractions; YC-1 (sGC activator) and inosine 3′,5′-cyclic monophosphate (cyclic IMP) caused a similar restoration. By contrast, in ODQ-treated preparations, cell-permeable guanosine 3′,5′-cyclic monophosphate (cyclic GMP) or inorganic pyrophosphate did not restore augmentation. UPLC-MS/MS measurements showed that thymoquinone augmented the intracellular content of cyclic IMP, but not that of cyclic GMP or adenosine 3′,5′-cyclic monophosphate. As the augmentation of contraction is reduced by PPADS (purinergic receptor antagonist), the switch in cyclic nucleotide production by sGC may be caused by activation of purinergic receptors on the arterial smooth muscle cells. The augmentation was prevented in porcine coronary arteries, but not in rat arteries, by HA-1077 and Y-27632 (Rho-kinase inhibitors) and nifedipine (L-type calcium channel inhibitor); in the latter, but not in the former it was reduced by ML-218 (T-type calcium channel inhibitor), demonstrating differences in blood vessel types in the impact of cyclic IMP on calcium handling. CONCLUSION Thymoquinone causes an endothelium-dependent augmentation of contractions of isolated arteries that requires endothelium-derived NO and sGC activation, but not the presence of cyclic GMP. It is explained by the production of cyclic IMP favoring the contractile process through alteration of calcium homeostasis.
Persistent Identifierhttp://hdl.handle.net/10722/229988
ISSN
2015 Impact Factor: 5.299
2015 SCImago Journal Rankings: 2.775

 

DC FieldValueLanguage
dc.contributor.authorDetremmerie, CMS-
dc.contributor.authorLeung, SWS-
dc.contributor.authorXu, A-
dc.contributor.authorGao, Y-
dc.contributor.authorVanhoutte, PM-
dc.date.accessioned2016-08-23T14:14:29Z-
dc.date.available2016-08-23T14:14:29Z-
dc.date.issued2016-
dc.identifier.citationThe 2016 Annual Meeting of the American Society of Pharmacology and Experimental (ASPET) held in conjunction with the Experimental Biology 2016 (EB 2016) Meeting, San Diego, CA., 2-6 April 2016. In The FASEB Journal, 2016, v. 30 Meeting Abstracts, no. 719.11-
dc.identifier.issn0892-6638-
dc.identifier.urihttp://hdl.handle.net/10722/229988-
dc.description.abstractOBJECTIVE To identify the mechanisms underlying the unexpected augmentation of contraction caused by thymoquinone, a natural compound with vasodilator properties, in isolated arteries. METHODS Ex vivo experiments were conducted in isolated mesenteric arteries and aortae of twelve to fourteen weeks old Sprague-Dawley rats and in porcine coronary arteries. The arteries were cut into rings (with or without endothelium) and suspended in organ chambers for isometric tension measurement in the absence and presence of pharmacological inhibitors. Following the establishment of an optimal basal tension, the preparations were contracted with phenylephrine (rat arteries) or serotonin (porcine arteries) and exposed to thymoquinone (10−7 to 10−3 M). Some rings were pooled for Western blotting of phosphorylated endothelial nitric oxide synthase (eNOS) and total eNOS or for the measurement of cyclic nucleotides levels with ultra-high performance liquid chromatography coupled with tandem mass spectrometry detection (UPLC-MS/MS). RESULTS In the three different arteries, thymoquinone caused a further concentration-dependent contraction, which was prevented by endothelium-removal. The augmentation of contraction was not significantly affected by anti-oxidants or by inhibitors of cyclooxygenases or endothelin-receptors. While Western blotting demonstrated increased phosphorylation of eNOS with thymoquinone, the augmentation was prevented by L-NAME [nitric oxide (NO) synthase inhibitor] and ODQ [soluble guanylyl cyclase (sGC) inhibitor]. In L-NAME-treated rings, the NO-donor diethylenetriamine NONOate restored or even increased thymoquinone-induced contractions; YC-1 (sGC activator) and inosine 3′,5′-cyclic monophosphate (cyclic IMP) caused a similar restoration. By contrast, in ODQ-treated preparations, cell-permeable guanosine 3′,5′-cyclic monophosphate (cyclic GMP) or inorganic pyrophosphate did not restore augmentation. UPLC-MS/MS measurements showed that thymoquinone augmented the intracellular content of cyclic IMP, but not that of cyclic GMP or adenosine 3′,5′-cyclic monophosphate. As the augmentation of contraction is reduced by PPADS (purinergic receptor antagonist), the switch in cyclic nucleotide production by sGC may be caused by activation of purinergic receptors on the arterial smooth muscle cells. The augmentation was prevented in porcine coronary arteries, but not in rat arteries, by HA-1077 and Y-27632 (Rho-kinase inhibitors) and nifedipine (L-type calcium channel inhibitor); in the latter, but not in the former it was reduced by ML-218 (T-type calcium channel inhibitor), demonstrating differences in blood vessel types in the impact of cyclic IMP on calcium handling. CONCLUSION Thymoquinone causes an endothelium-dependent augmentation of contractions of isolated arteries that requires endothelium-derived NO and sGC activation, but not the presence of cyclic GMP. It is explained by the production of cyclic IMP favoring the contractile process through alteration of calcium homeostasis.-
dc.languageeng-
dc.publisherFederation of American Societies for Experimental Biology. The Journal's web site is located at http://www.fasebj.org/-
dc.relation.ispartofThe FASEB Journal-
dc.titleBiased activation of soluble Guanylyl Cyclase can cause contraction of isolated arteries-
dc.typeConference_Paper-
dc.identifier.emailLeung, SWS: swsleung@hku.hk-
dc.identifier.emailXu, A: amxu@hkucc.hku.hk-
dc.identifier.emailVanhoutte, PM: vanhoutt@hku.hk-
dc.identifier.authorityLeung, SWS=rp00235-
dc.identifier.authorityXu, A=rp00485-
dc.identifier.authorityVanhoutte, PM=rp00238-
dc.identifier.hkuros262193-
dc.identifier.volume30-
dc.identifier.issueMeeting Abstracts-
dc.publisher.placeUnited States-

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