Pharmacological analysis of the haemodynamic effects of 5‐HT 1B/D receptor agonists in the normotensive rat

Pharmacological analysis of the haemodynamic effects of 5‐HT 1B/D receptor agonists in the normotensive rat

The receptors involved in mediating the haemodynamic effects of three 5‐HT 1B/D receptor agonists were investigated in pentobarbitone anaesthetized rats ( n =6–17 per group). Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 μg kg −1 ; each dose over 5 min) in...

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Veröffentlicht in:British journal of pharmacology 2009-02, Vol.123 (2), p.205-214
Hauptverfasser: Pagniez, Fabrice, Valentin, Jean‐Pierre, Vieu, Sylvie, Colpaert, Francis C, John, Gareth W
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Valentin, Jean‐Pierre
Vieu, Sylvie
Colpaert, Francis C
John, Gareth W
description The receptors involved in mediating the haemodynamic effects of three 5‐HT 1B/D receptor agonists were investigated in pentobarbitone anaesthetized rats ( n =6–17 per group). Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 μg kg −1 ; each dose over 5 min) induced dose‐dependent and marked hypotension (−42±6 and −34±4 mmHg at the highest dose, respectively; both P
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Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 μg kg −1 ; each dose over 5 min) induced dose‐dependent and marked hypotension (−42±6 and −34±4 mmHg at the highest dose, respectively; both P <0.05 vs vehicle: +5±3 mmHg) and bradycardia (−85±16 and −44±12 beats min −1 at the highest dose, respectively; both P <0.05 vs vehicle: +16±6 beats min −1 ). Zolmitriptan evoked only moderate hypotension at the highest dose (−19±9 mmHg; P <0.05 vs vehicle). A high dose of the 5‐HT 1B/D receptor antagonist, GR 127935 (0.63 mg kg −1 , i.v.), failed to antagonize the hypotension and bradycardia evoked by sumatriptan (−35±6 mmHg and −52±19 beats min −1 , respectively; both not significant vs sumatriptan in untreated rats), but moderately reduced the hypotension and bradycardia evoked by rizatriptan (−20±5 mmHg and −30±17 beats min −1 , respectively; both P <0.05 vs vehicle and vs rizatriptan in untreated rats). The selective 5‐HT 1A receptor antagonist, WAY 100635 (0.16 and 0.63 mg kg −1 , i.v.), dose‐dependently attenuated the haemodynamic responses evoked by rizatriptan and sumatriptan, which were almost abolished by the higher dose of WAY 100635 (−4±3 mmHg and −15±8 beats min −1 ; both not significant vs vehicle and P <0.05 vs rizatriptan in untreated rats). A slight but statistically significant reduction in mean arterial pressure (MAP) persisted at the highest dose of sumatriptan (−13±4 mmHg following the higher dose of WAY 100635; P <0.05 vs vehicle). In pithed rats with MAP normalized by angiotensin II, rizatriptan failed to induce hypotension or bradycardia (+5±4 mmHg and −6±16 beats min −1 , respectively; both NS vs vehicle and P <0.05 vs rizatriptan in untreated rats). Similarly, sumatriptan failed to induce bradycardia in pithed rats (+5±6 beats min −1 ; not significant vs vehicle and P <0.05 vs sumatriptan in untreated rats), whereas a slight but statistically significant reduction in MAP, compared to controls, occurred at the highest dose (−9±9 mmHg; P <0.05 vs both vehicle and sumatriptan in untreated rats). In bilaterally vagotomized and atropine‐treated (1 mg kg −1 , i.v.) rats, the reductions in MAP and heart rate evoked by rizatriptan (−31±4 mmHg and −64 ±9 beats min −1 , respectively; both P <0.05 vs vehicle and not significant vs rizatriptan in controls) and sumatriptan (−47±8 mmHg and −56±10 beats min −1 , respectively; both P <0.05 vs vehicle and not significant vs sumatriptan in controls) were not statistically significantly different from those observed in controls. In conclusion, the 5‐HT 1B/D receptor agonists, rizatriptan and sumatriptan, elicit hypotension and bradycardia in the normotensive anaesthetized rat predominantly via activation of central 5‐HT 1A receptors, and a consequent reduction in sympathetic outflow. British Journal of Pharmacology (1998) 123 , 205–214; doi: 10.1038/sj.bjp.0701593]]></description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1038/sj.bjp.0701593</identifier><language>eng</language><ispartof>British journal of pharmacology, 2009-02, Vol.123 (2), p.205-214</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c843-7f8aba19fe50720e94ccddd43b3519c9467742a3bf9827aa44ef7f4b9c63da1a3</citedby><cites>FETCH-LOGICAL-c843-7f8aba19fe50720e94ccddd43b3519c9467742a3bf9827aa44ef7f4b9c63da1a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Pagniez, Fabrice</creatorcontrib><creatorcontrib>Valentin, Jean‐Pierre</creatorcontrib><creatorcontrib>Vieu, Sylvie</creatorcontrib><creatorcontrib>Colpaert, Francis C</creatorcontrib><creatorcontrib>John, Gareth W</creatorcontrib><title>Pharmacological analysis of the haemodynamic effects of 5‐HT 1B/D receptor agonists in the normotensive rat</title><title>British journal of pharmacology</title><description><![CDATA[The receptors involved in mediating the haemodynamic effects of three 5‐HT 1B/D receptor agonists were investigated in pentobarbitone anaesthetized rats ( n =6–17 per group). Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 μg kg −1 ; each dose over 5 min) induced dose‐dependent and marked hypotension (−42±6 and −34±4 mmHg at the highest dose, respectively; both P <0.05 vs vehicle: +5±3 mmHg) and bradycardia (−85±16 and −44±12 beats min −1 at the highest dose, respectively; both P <0.05 vs vehicle: +16±6 beats min −1 ). Zolmitriptan evoked only moderate hypotension at the highest dose (−19±9 mmHg; P <0.05 vs vehicle). A high dose of the 5‐HT 1B/D receptor antagonist, GR 127935 (0.63 mg kg −1 , i.v.), failed to antagonize the hypotension and bradycardia evoked by sumatriptan (−35±6 mmHg and −52±19 beats min −1 , respectively; both not significant vs sumatriptan in untreated rats), but moderately reduced the hypotension and bradycardia evoked by rizatriptan (−20±5 mmHg and −30±17 beats min −1 , respectively; both P <0.05 vs vehicle and vs rizatriptan in untreated rats). The selective 5‐HT 1A receptor antagonist, WAY 100635 (0.16 and 0.63 mg kg −1 , i.v.), dose‐dependently attenuated the haemodynamic responses evoked by rizatriptan and sumatriptan, which were almost abolished by the higher dose of WAY 100635 (−4±3 mmHg and −15±8 beats min −1 ; both not significant vs vehicle and P <0.05 vs rizatriptan in untreated rats). A slight but statistically significant reduction in mean arterial pressure (MAP) persisted at the highest dose of sumatriptan (−13±4 mmHg following the higher dose of WAY 100635; P <0.05 vs vehicle). In pithed rats with MAP normalized by angiotensin II, rizatriptan failed to induce hypotension or bradycardia (+5±4 mmHg and −6±16 beats min −1 , respectively; both NS vs vehicle and P <0.05 vs rizatriptan in untreated rats). Similarly, sumatriptan failed to induce bradycardia in pithed rats (+5±6 beats min −1 ; not significant vs vehicle and P <0.05 vs sumatriptan in untreated rats), whereas a slight but statistically significant reduction in MAP, compared to controls, occurred at the highest dose (−9±9 mmHg; P <0.05 vs both vehicle and sumatriptan in untreated rats). In bilaterally vagotomized and atropine‐treated (1 mg kg −1 , i.v.) rats, the reductions in MAP and heart rate evoked by rizatriptan (−31±4 mmHg and −64 ±9 beats min −1 , respectively; both P <0.05 vs vehicle and not significant vs rizatriptan in controls) and sumatriptan (−47±8 mmHg and −56±10 beats min −1 , respectively; both P <0.05 vs vehicle and not significant vs sumatriptan in controls) were not statistically significantly different from those observed in controls. In conclusion, the 5‐HT 1B/D receptor agonists, rizatriptan and sumatriptan, elicit hypotension and bradycardia in the normotensive anaesthetized rat predominantly via activation of central 5‐HT 1A receptors, and a consequent reduction in sympathetic outflow. British Journal of Pharmacology (1998) 123 , 205–214; doi: 10.1038/sj.bjp.0701593]]></description><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNotkL1OwzAUhS0EEqWwMvsFktq1E9sjlJ8iVYIhe3TjXLeOkriyI6RuPALPyJNQSqczfOec4SPknrOcM6EXqcubbp8zxXhhxAWZcanKrBCaX5IZY0xlnGt9TW5S6hg7QlXMyPCxgziADX3Yegs9hRH6Q_KJBkenHdId4BDawwiDtxSdQzudWPHz9b2uKH9cPNGIFvdTiBS2YfTpWPDjaTyGOIQJx-Q_kUaYbsmVgz7h3TnnpHp5rlbrbPP--rZ62GRWS5Epp6EBbhwWTC0ZGmlt27ZSNKLgxhpZKiWXIBpn9FIBSIlOOdkYW4oWOIg5yf9vbQwpRXT1PvoB4qHmrP5zVaeuPrqqz67EL7ESYH0</recordid><startdate>20090203</startdate><enddate>20090203</enddate><creator>Pagniez, Fabrice</creator><creator>Valentin, Jean‐Pierre</creator><creator>Vieu, Sylvie</creator><creator>Colpaert, Francis C</creator><creator>John, Gareth W</creator><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20090203</creationdate><title>Pharmacological analysis of the haemodynamic effects of 5‐HT 1B/D receptor agonists in the normotensive rat</title><author>Pagniez, Fabrice ; Valentin, Jean‐Pierre ; Vieu, Sylvie ; Colpaert, Francis C ; John, Gareth W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c843-7f8aba19fe50720e94ccddd43b3519c9467742a3bf9827aa44ef7f4b9c63da1a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pagniez, Fabrice</creatorcontrib><creatorcontrib>Valentin, Jean‐Pierre</creatorcontrib><creatorcontrib>Vieu, Sylvie</creatorcontrib><creatorcontrib>Colpaert, Francis C</creatorcontrib><creatorcontrib>John, Gareth W</creatorcontrib><collection>CrossRef</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pagniez, Fabrice</au><au>Valentin, Jean‐Pierre</au><au>Vieu, Sylvie</au><au>Colpaert, Francis C</au><au>John, Gareth W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacological analysis of the haemodynamic effects of 5‐HT 1B/D receptor agonists in the normotensive rat</atitle><jtitle>British journal of pharmacology</jtitle><date>2009-02-03</date><risdate>2009</risdate><volume>123</volume><issue>2</issue><spage>205</spage><epage>214</epage><pages>205-214</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><abstract><![CDATA[The receptors involved in mediating the haemodynamic effects of three 5‐HT 1B/D receptor agonists were investigated in pentobarbitone anaesthetized rats ( n =6–17 per group). Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 μg kg −1 ; each dose over 5 min) induced dose‐dependent and marked hypotension (−42±6 and −34±4 mmHg at the highest dose, respectively; both P <0.05 vs vehicle: +5±3 mmHg) and bradycardia (−85±16 and −44±12 beats min −1 at the highest dose, respectively; both P <0.05 vs vehicle: +16±6 beats min −1 ). Zolmitriptan evoked only moderate hypotension at the highest dose (−19±9 mmHg; P <0.05 vs vehicle). A high dose of the 5‐HT 1B/D receptor antagonist, GR 127935 (0.63 mg kg −1 , i.v.), failed to antagonize the hypotension and bradycardia evoked by sumatriptan (−35±6 mmHg and −52±19 beats min −1 , respectively; both not significant vs sumatriptan in untreated rats), but moderately reduced the hypotension and bradycardia evoked by rizatriptan (−20±5 mmHg and −30±17 beats min −1 , respectively; both P <0.05 vs vehicle and vs rizatriptan in untreated rats). The selective 5‐HT 1A receptor antagonist, WAY 100635 (0.16 and 0.63 mg kg −1 , i.v.), dose‐dependently attenuated the haemodynamic responses evoked by rizatriptan and sumatriptan, which were almost abolished by the higher dose of WAY 100635 (−4±3 mmHg and −15±8 beats min −1 ; both not significant vs vehicle and P <0.05 vs rizatriptan in untreated rats). A slight but statistically significant reduction in mean arterial pressure (MAP) persisted at the highest dose of sumatriptan (−13±4 mmHg following the higher dose of WAY 100635; P <0.05 vs vehicle). In pithed rats with MAP normalized by angiotensin II, rizatriptan failed to induce hypotension or bradycardia (+5±4 mmHg and −6±16 beats min −1 , respectively; both NS vs vehicle and P <0.05 vs rizatriptan in untreated rats). Similarly, sumatriptan failed to induce bradycardia in pithed rats (+5±6 beats min −1 ; not significant vs vehicle and P <0.05 vs sumatriptan in untreated rats), whereas a slight but statistically significant reduction in MAP, compared to controls, occurred at the highest dose (−9±9 mmHg; P <0.05 vs both vehicle and sumatriptan in untreated rats). In bilaterally vagotomized and atropine‐treated (1 mg kg −1 , i.v.) rats, the reductions in MAP and heart rate evoked by rizatriptan (−31±4 mmHg and −64 ±9 beats min −1 , respectively; both P <0.05 vs vehicle and not significant vs rizatriptan in controls) and sumatriptan (−47±8 mmHg and −56±10 beats min −1 , respectively; both P <0.05 vs vehicle and not significant vs sumatriptan in controls) were not statistically significantly different from those observed in controls. In conclusion, the 5‐HT 1B/D receptor agonists, rizatriptan and sumatriptan, elicit hypotension and bradycardia in the normotensive anaesthetized rat predominantly via activation of central 5‐HT 1A receptors, and a consequent reduction in sympathetic outflow. British Journal of Pharmacology (1998) 123 , 205–214; doi: 10.1038/sj.bjp.0701593]]></abstract><doi>10.1038/sj.bjp.0701593</doi><tpages>10</tpages></addata></record>
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title Pharmacological analysis of the haemodynamic effects of 5‐HT 1B/D receptor agonists in the normotensive rat
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