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Relaxation effect of narirutin on rat mesenteric arteries via nitric oxide release and activation of voltage-gated potassium channels
Narirutin is one of the most common flavanones found in citrus fruits. The vascular effects of its analogues naringenin and naringin have been reported but its effects on the cardiovascular system are largely unknown. In this study, relaxation effect of narirutin and its mechanisms of action were in...
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| Published in: | European journal of pharmacology 2021-08, Vol.905, p.174190-174190, Article 174190 |
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| creator | Wong, Emily Sze-Wan Li, Rachel Wai-Sum Li, Jingjing Li, Renkai Seto, Sai-Wang Lee, Simon Ming-Yuen Leung, George Pak-Heng |
| description | Narirutin is one of the most common flavanones found in citrus fruits. The vascular effects of its analogues naringenin and naringin have been reported but its effects on the cardiovascular system are largely unknown. In this study, relaxation effect of narirutin and its mechanisms of action were investigated by measuring isometric tension in rat mesenteric arteries. Patch-clamping was also used to study the effect of narirutin on potassium channels in vascular smooth muscle cells. Moreover, its effects on phosphorylation of endothelial nitric oxide synthase, cAMP level and phosphodiesterase activity in rat mesenteric arteries were studied by Western blot and biochemical assays. The results showed that pre-incubation of rat mesenteric arteries with narirutin had no influence on acetylcholine-induced endothelial-dependent relaxation. However, narirutin caused a direct concentration-dependent relaxation in rat mesenteric arteries. This relaxation effect was comparable to that of narirutin's structural analogue naringenin. Narirutin-induced relaxation was reduced by the removal of endothelium, NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor), and 4-aminopyridine (a voltage-gated potassium channel blocker). In addition, narirutin increased the phosphorylation of endothelial nitric oxide synthase and increased the voltage-dependent potassium current in mesenteric arterial smooth muscle cells. These effects were abolished by protein kinase A inhibitor. Furthermore, narirutin could increase cAMP level and inhibit phosphodiesterase activity in rat mesenteric arteries. In conclusion, narirutin has vasorelaxing effect and the mechanism involves the inhibition of phosphodiesterase, which increases intracellular cAMP, thereby stimulating the endothelial nitric oxide synthase and activating the voltage-gated potassium channels in vascular smooth muscle cells. |
| doi_str_mv | 10.1016/j.ejphar.2021.174190 |
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The vascular effects of its analogues naringenin and naringin have been reported but its effects on the cardiovascular system are largely unknown. In this study, relaxation effect of narirutin and its mechanisms of action were investigated by measuring isometric tension in rat mesenteric arteries. Patch-clamping was also used to study the effect of narirutin on potassium channels in vascular smooth muscle cells. Moreover, its effects on phosphorylation of endothelial nitric oxide synthase, cAMP level and phosphodiesterase activity in rat mesenteric arteries were studied by Western blot and biochemical assays. The results showed that pre-incubation of rat mesenteric arteries with narirutin had no influence on acetylcholine-induced endothelial-dependent relaxation. However, narirutin caused a direct concentration-dependent relaxation in rat mesenteric arteries. This relaxation effect was comparable to that of narirutin's structural analogue naringenin. Narirutin-induced relaxation was reduced by the removal of endothelium, NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor), and 4-aminopyridine (a voltage-gated potassium channel blocker). In addition, narirutin increased the phosphorylation of endothelial nitric oxide synthase and increased the voltage-dependent potassium current in mesenteric arterial smooth muscle cells. These effects were abolished by protein kinase A inhibitor. Furthermore, narirutin could increase cAMP level and inhibit phosphodiesterase activity in rat mesenteric arteries. In conclusion, narirutin has vasorelaxing effect and the mechanism involves the inhibition of phosphodiesterase, which increases intracellular cAMP, thereby stimulating the endothelial nitric oxide synthase and activating the voltage-gated potassium channels in vascular smooth muscle cells.</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2021.174190</identifier><identifier>PMID: 34015322</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Animals ; Cyclic AMP - metabolism ; Disaccharides - pharmacology ; Endothelium ; Endothelium, Vascular - drug effects ; Enzyme Inhibitors - pharmacology ; Flavanones - pharmacology ; Male ; Mesenteric Arteries - drug effects ; Muscle Relaxation - drug effects ; Muscle, Smooth, Vascular - drug effects ; Narirutin ; Nitric oxide ; Nitric Oxide - metabolism ; Nitric Oxide Synthase Type III - metabolism ; Phosphoric Diester Hydrolases - metabolism ; Potassium Channel Blockers - pharmacology ; Potassium Channels, Voltage-Gated - agonists ; Rats ; Rats, Sprague-Dawley ; Relaxation ; Vasodilator Agents - pharmacology ; Voltage-gated potassium channels</subject><ispartof>European journal of pharmacology, 2021-08, Vol.905, p.174190-174190, Article 174190</ispartof><rights>2021 Elsevier B.V.</rights><rights>Copyright © 2021 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-1e8531106346fb4c39062b8948db9b74104ff737a38b5a56f98237d1eb5c8f233</citedby><cites>FETCH-LOGICAL-c362t-1e8531106346fb4c39062b8948db9b74104ff737a38b5a56f98237d1eb5c8f233</cites><orcidid>0000-0001-9770-2591 ; 0000-0001-7030-2299</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34015322$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wong, Emily Sze-Wan</creatorcontrib><creatorcontrib>Li, Rachel Wai-Sum</creatorcontrib><creatorcontrib>Li, Jingjing</creatorcontrib><creatorcontrib>Li, Renkai</creatorcontrib><creatorcontrib>Seto, Sai-Wang</creatorcontrib><creatorcontrib>Lee, Simon Ming-Yuen</creatorcontrib><creatorcontrib>Leung, George Pak-Heng</creatorcontrib><title>Relaxation effect of narirutin on rat mesenteric arteries via nitric oxide release and activation of voltage-gated potassium channels</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>Narirutin is one of the most common flavanones found in citrus fruits. The vascular effects of its analogues naringenin and naringin have been reported but its effects on the cardiovascular system are largely unknown. In this study, relaxation effect of narirutin and its mechanisms of action were investigated by measuring isometric tension in rat mesenteric arteries. Patch-clamping was also used to study the effect of narirutin on potassium channels in vascular smooth muscle cells. Moreover, its effects on phosphorylation of endothelial nitric oxide synthase, cAMP level and phosphodiesterase activity in rat mesenteric arteries were studied by Western blot and biochemical assays. The results showed that pre-incubation of rat mesenteric arteries with narirutin had no influence on acetylcholine-induced endothelial-dependent relaxation. However, narirutin caused a direct concentration-dependent relaxation in rat mesenteric arteries. This relaxation effect was comparable to that of narirutin's structural analogue naringenin. Narirutin-induced relaxation was reduced by the removal of endothelium, NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor), and 4-aminopyridine (a voltage-gated potassium channel blocker). In addition, narirutin increased the phosphorylation of endothelial nitric oxide synthase and increased the voltage-dependent potassium current in mesenteric arterial smooth muscle cells. These effects were abolished by protein kinase A inhibitor. Furthermore, narirutin could increase cAMP level and inhibit phosphodiesterase activity in rat mesenteric arteries. In conclusion, narirutin has vasorelaxing effect and the mechanism involves the inhibition of phosphodiesterase, which increases intracellular cAMP, thereby stimulating the endothelial nitric oxide synthase and activating the voltage-gated potassium channels in vascular smooth muscle cells.</description><subject>Animals</subject><subject>Cyclic AMP - metabolism</subject><subject>Disaccharides - pharmacology</subject><subject>Endothelium</subject><subject>Endothelium, Vascular - drug effects</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Flavanones - pharmacology</subject><subject>Male</subject><subject>Mesenteric Arteries - drug effects</subject><subject>Muscle Relaxation - drug effects</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Narirutin</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Synthase Type III - metabolism</subject><subject>Phosphoric Diester Hydrolases - metabolism</subject><subject>Potassium Channel Blockers - pharmacology</subject><subject>Potassium Channels, Voltage-Gated - agonists</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Relaxation</subject><subject>Vasodilator Agents - pharmacology</subject><subject>Voltage-gated potassium channels</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kc2KFTEQhYMozp3RNxDJ0k1f89c_2QgyjDowIIiuQ3W6MpNLd3JN0pfxAXxvc-nRpauC4pyvqHMIecPZnjPevT_s8XB8gLQXTPA97xXX7BnZ8aHXDeu5eE52jHHVCK31BbnM-cAYa7VoX5ILqRhvpRA78vsbzvAIxcdA0Tm0hUZHAySf1uIDresEhS6YMRRM3lJI54mZnjzQ4Mt5Fx_9hDThjJCRQpgo2OJPG7byTnEucI_NPRSc6DEWyNmvC7UPEALO-RV54WDO-PppXpEfn26-X39p7r5-vr3-eNdY2YnScBxayTnrpOrcqKzUrBPjoNUwjXqsCTDlXC97kMPYQts5PQjZTxzH1g5OSHlF3m3cY4o_V8zFLD5bnGcIGNdsRMULoSqoStUmtSnmnNCZY_ILpF-GM3MuwBzMVoA5F2C2Aqrt7dOFdVxw-mf6m3gVfNgE9W08eUwmW4_B4uRTTd9M0f__wh8Qo5pq</recordid><startdate>20210815</startdate><enddate>20210815</enddate><creator>Wong, Emily Sze-Wan</creator><creator>Li, Rachel Wai-Sum</creator><creator>Li, Jingjing</creator><creator>Li, Renkai</creator><creator>Seto, Sai-Wang</creator><creator>Lee, Simon Ming-Yuen</creator><creator>Leung, George Pak-Heng</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-9770-2591</orcidid><orcidid>https://orcid.org/0000-0001-7030-2299</orcidid></search><sort><creationdate>20210815</creationdate><title>Relaxation effect of narirutin on rat mesenteric arteries via nitric oxide release and activation of voltage-gated potassium channels</title><author>Wong, Emily Sze-Wan ; Li, Rachel Wai-Sum ; Li, Jingjing ; Li, Renkai ; Seto, Sai-Wang ; Lee, Simon Ming-Yuen ; Leung, George Pak-Heng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-1e8531106346fb4c39062b8948db9b74104ff737a38b5a56f98237d1eb5c8f233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Cyclic AMP - metabolism</topic><topic>Disaccharides - pharmacology</topic><topic>Endothelium</topic><topic>Endothelium, Vascular - drug effects</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Flavanones - pharmacology</topic><topic>Male</topic><topic>Mesenteric Arteries - drug effects</topic><topic>Muscle Relaxation - drug effects</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Narirutin</topic><topic>Nitric oxide</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric Oxide Synthase Type III - metabolism</topic><topic>Phosphoric Diester Hydrolases - metabolism</topic><topic>Potassium Channel Blockers - pharmacology</topic><topic>Potassium Channels, Voltage-Gated - agonists</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Relaxation</topic><topic>Vasodilator Agents - pharmacology</topic><topic>Voltage-gated potassium channels</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wong, Emily Sze-Wan</creatorcontrib><creatorcontrib>Li, Rachel Wai-Sum</creatorcontrib><creatorcontrib>Li, Jingjing</creatorcontrib><creatorcontrib>Li, Renkai</creatorcontrib><creatorcontrib>Seto, Sai-Wang</creatorcontrib><creatorcontrib>Lee, Simon Ming-Yuen</creatorcontrib><creatorcontrib>Leung, George Pak-Heng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wong, Emily Sze-Wan</au><au>Li, Rachel Wai-Sum</au><au>Li, Jingjing</au><au>Li, Renkai</au><au>Seto, Sai-Wang</au><au>Lee, Simon Ming-Yuen</au><au>Leung, George Pak-Heng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Relaxation effect of narirutin on rat mesenteric arteries via nitric oxide release and activation of voltage-gated potassium channels</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2021-08-15</date><risdate>2021</risdate><volume>905</volume><spage>174190</spage><epage>174190</epage><pages>174190-174190</pages><artnum>174190</artnum><issn>0014-2999</issn><eissn>1879-0712</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Narirutin is one of the most common flavanones found in citrus fruits. The vascular effects of its analogues naringenin and naringin have been reported but its effects on the cardiovascular system are largely unknown. In this study, relaxation effect of narirutin and its mechanisms of action were investigated by measuring isometric tension in rat mesenteric arteries. Patch-clamping was also used to study the effect of narirutin on potassium channels in vascular smooth muscle cells. Moreover, its effects on phosphorylation of endothelial nitric oxide synthase, cAMP level and phosphodiesterase activity in rat mesenteric arteries were studied by Western blot and biochemical assays. The results showed that pre-incubation of rat mesenteric arteries with narirutin had no influence on acetylcholine-induced endothelial-dependent relaxation. However, narirutin caused a direct concentration-dependent relaxation in rat mesenteric arteries. This relaxation effect was comparable to that of narirutin's structural analogue naringenin. Narirutin-induced relaxation was reduced by the removal of endothelium, NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor), and 4-aminopyridine (a voltage-gated potassium channel blocker). In addition, narirutin increased the phosphorylation of endothelial nitric oxide synthase and increased the voltage-dependent potassium current in mesenteric arterial smooth muscle cells. These effects were abolished by protein kinase A inhibitor. Furthermore, narirutin could increase cAMP level and inhibit phosphodiesterase activity in rat mesenteric arteries. In conclusion, narirutin has vasorelaxing effect and the mechanism involves the inhibition of phosphodiesterase, which increases intracellular cAMP, thereby stimulating the endothelial nitric oxide synthase and activating the voltage-gated potassium channels in vascular smooth muscle cells.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>34015322</pmid><doi>10.1016/j.ejphar.2021.174190</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0001-9770-2591</orcidid><orcidid>https://orcid.org/0000-0001-7030-2299</orcidid></addata></record> |
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| subjects | Animals Cyclic AMP - metabolism Disaccharides - pharmacology Endothelium Endothelium, Vascular - drug effects Enzyme Inhibitors - pharmacology Flavanones - pharmacology Male Mesenteric Arteries - drug effects Muscle Relaxation - drug effects Muscle, Smooth, Vascular - drug effects Narirutin Nitric oxide Nitric Oxide - metabolism Nitric Oxide Synthase Type III - metabolism Phosphoric Diester Hydrolases - metabolism Potassium Channel Blockers - pharmacology Potassium Channels, Voltage-Gated - agonists Rats Rats, Sprague-Dawley Relaxation Vasodilator Agents - pharmacology Voltage-gated potassium channels |
| title | Relaxation effect of narirutin on rat mesenteric arteries via nitric oxide release and activation of voltage-gated potassium channels |
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