Effects of the non‐peptide B 2 antagonist FR173657 on kinin‐induced smooth muscle contraction and relaxation, vasoconstriction and prostaglandin release
The non‐peptide bradykinin (BK) antagonist (E)‐3‐(6‐acetamido‐3‐pyridyl)‐N‐[N‐[2,4‐dichloro‐3‐[(2‐ methyl‐8‐quinolinyl)oxymethyl]phenyl]‐N‐methylaminocarbonylmethyl]acrylamide (FR173657) was tested in intestinal, uterine, tracheal and vascular in vitro preparations. The investigation aimed at determ...
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| Veröffentlicht in: | British journal of pharmacology 2009-02, Vol.121 (3), p.469-476 |
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| creator | Griesbacher, Thomas Sametz, Wolfgang Legat, Franz J. Diethart, Sabine Hammer, Susanne Juan, Heinz |
| description | The non‐peptide bradykinin (BK) antagonist (E)‐3‐(6‐acetamido‐3‐pyridyl)‐N‐[N‐[2,4‐dichloro‐3‐[(2‐ methyl‐8‐quinolinyl)oxymethyl]phenyl]‐N‐methylaminocarbonylmethyl]acrylamide (FR173657) was tested in intestinal, uterine, tracheal and vascular
in vitro
preparations. The investigation aimed at determining the antagonistic potency, duration of action, specificity for BK receptors and apparent mode of antagonistic action of FR173657.
Contractions of the isolated ileum of the guinea‐pig in response to BK were inhibited by FR173657 (10–300 n
M
) in a concentration‐dependent manner. The inhibition lasted for up to 90 min after wash‐out of FR173657. Cumulative concentration‐response curves to BK were shifted to the right with a concomitant decrease in the maximum effect. A p
K
B
value of 8.7 was determined. FR173657 had no effect on contractions induced by acetylcholine, histamine, 5‐hydroxytryptamine, substance P, angiotensin II or caerulein.
The concentration‐response curves for B
2
receptor‐mediated relaxations of the rat isolated duodenum induced by BK were shifted to the right together with a concomitant reduction of the maximum BK effect in the presence of FR173657 (10–300 n
M
). A p
K
B
of 9.0±0.2 was calculated. FR173657 had no effect on B
1
receptor‐mediated relaxations in response to des‐Arg
9
‐BK.
The concentration‐response curves for BK‐induced contractions of the rat isolated uterus were shifted to the right by FR173657 (3–300 n
M
) in a concentration‐dependent and parallel manner. The Schild plot for the inhibition caused by FR173657 had a slope of −0.98 indicating a competitive mode of antagonism. A pA
2
value of 9.1 was determined.
Contractions of the circular smooth muscles of the guinea‐pig isolated trachea in response to BK were concentration‐dependently inhibited by FR173657 (10–100 n
M
). An affinity estimate of 9.3 was calculated for FR173657. Contractions induced by acetylcholine and relaxations in response to isoprenaline remained completely unaffected by FR173657.
In the rabbit isolated perfused ear, BK (0.01–10 nmol) produced a dose‐dependent vasoconstriction. In the presence of 30 n
M
FR173657, the effects of BK were reduced by at least 60%, while FR173657 completely abolished the effects of all BK doses at 300 n
M
. FR173657 did not affect vasoconstriction induced by noradrenaline or angiotensin II.
The arterial injection of BK (10 nmol) into the rabbit isolated perfused ear caused an approximately three fold increase in the release of |
| doi_str_mv | 10.1038/sj.bjp.0701159 |
| format | Article |
| fullrecord | <record><control><sourceid>crossref</sourceid><recordid>TN_cdi_crossref_primary_10_1038_sj_bjp_0701159</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>10_1038_sj_bjp_0701159</sourcerecordid><originalsourceid>FETCH-LOGICAL-c169t-8e5756df762d9862c30b81d2880bd0bd684745535b77ec1da35e7e0233cc22f83</originalsourceid><addsrcrecordid>eNpFkMFKAzEQhoMoWKtXz3kAd002zSY9ammrUBBEz0s2mbVZt8mySUVvPoIP4NP5JGaxIAzMDP_H_MOP0CUlOSVMXoc2r9s-J4JQyudHaEJnosw4k_QYTQghIqNUylN0FkJLSBIFn6DvZdOAjgH7BsctYOfdz-dXD320BvAtLrByUb14Z0PEq0cqWMkF9g6_WmdH1Dqz12Bw2Hkft3i3D7oDrL2Lg9LRJlI5gwfo1Lsa1yv8poJPeoiD_Qf6wYfk06XZuhEHFeAcnTSqC3Bx6FP0vFo-Le6yzcP6fnGzyTQt5zGTwAUvTSPKwsxlWWhGaklNISWpTapSzsSMc8ZrIUBToxgHAaRgTOuiaCSbovzvrk5fhAGaqh_sTg0fFSXVmG0V2iplWx2yZb9g8XJj</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Effects of the non‐peptide B 2 antagonist FR173657 on kinin‐induced smooth muscle contraction and relaxation, vasoconstriction and prostaglandin release</title><source>Wiley Online Library Free Content</source><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Griesbacher, Thomas ; Sametz, Wolfgang ; Legat, Franz J. ; Diethart, Sabine ; Hammer, Susanne ; Juan, Heinz</creator><creatorcontrib>Griesbacher, Thomas ; Sametz, Wolfgang ; Legat, Franz J. ; Diethart, Sabine ; Hammer, Susanne ; Juan, Heinz</creatorcontrib><description>The non‐peptide bradykinin (BK) antagonist (E)‐3‐(6‐acetamido‐3‐pyridyl)‐N‐[N‐[2,4‐dichloro‐3‐[(2‐ methyl‐8‐quinolinyl)oxymethyl]phenyl]‐N‐methylaminocarbonylmethyl]acrylamide (FR173657) was tested in intestinal, uterine, tracheal and vascular
in vitro
preparations. The investigation aimed at determining the antagonistic potency, duration of action, specificity for BK receptors and apparent mode of antagonistic action of FR173657.
Contractions of the isolated ileum of the guinea‐pig in response to BK were inhibited by FR173657 (10–300 n
M
) in a concentration‐dependent manner. The inhibition lasted for up to 90 min after wash‐out of FR173657. Cumulative concentration‐response curves to BK were shifted to the right with a concomitant decrease in the maximum effect. A p
K
B
value of 8.7 was determined. FR173657 had no effect on contractions induced by acetylcholine, histamine, 5‐hydroxytryptamine, substance P, angiotensin II or caerulein.
The concentration‐response curves for B
2
receptor‐mediated relaxations of the rat isolated duodenum induced by BK were shifted to the right together with a concomitant reduction of the maximum BK effect in the presence of FR173657 (10–300 n
M
). A p
K
B
of 9.0±0.2 was calculated. FR173657 had no effect on B
1
receptor‐mediated relaxations in response to des‐Arg
9
‐BK.
The concentration‐response curves for BK‐induced contractions of the rat isolated uterus were shifted to the right by FR173657 (3–300 n
M
) in a concentration‐dependent and parallel manner. The Schild plot for the inhibition caused by FR173657 had a slope of −0.98 indicating a competitive mode of antagonism. A pA
2
value of 9.1 was determined.
Contractions of the circular smooth muscles of the guinea‐pig isolated trachea in response to BK were concentration‐dependently inhibited by FR173657 (10–100 n
M
). An affinity estimate of 9.3 was calculated for FR173657. Contractions induced by acetylcholine and relaxations in response to isoprenaline remained completely unaffected by FR173657.
In the rabbit isolated perfused ear, BK (0.01–10 nmol) produced a dose‐dependent vasoconstriction. In the presence of 30 n
M
FR173657, the effects of BK were reduced by at least 60%, while FR173657 completely abolished the effects of all BK doses at 300 n
M
. FR173657 did not affect vasoconstriction induced by noradrenaline or angiotensin II.
The arterial injection of BK (10 nmol) into the rabbit isolated perfused ear caused an approximately three fold increase in the release of the prostaglandins E
2
and I
2
into the venous effluent. The BK‐stimulated prostaglandin release was completely abolished in the presence of FR173657 (300 n
M
) while the basal prostaglandin release was unchanged.
In summary, FR173657 was shown to be a highly potent and selective BK antagonist which was active on B
2
, but not B
1
, receptors. FR173657 was a competitive antagonist in the rat uterus but showed a deviation from competitive inhibition in the other preparations studied similar to other second generation peptide antagonists. The inhibitory action
in vitro
was long‐lasting, but was fully reversible.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1038/sj.bjp.0701159</identifier><language>eng</language><ispartof>British journal of pharmacology, 2009-02, Vol.121 (3), p.469-476</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c169t-8e5756df762d9862c30b81d2880bd0bd684745535b77ec1da35e7e0233cc22f83</citedby><cites>FETCH-LOGICAL-c169t-8e5756df762d9862c30b81d2880bd0bd684745535b77ec1da35e7e0233cc22f83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Griesbacher, Thomas</creatorcontrib><creatorcontrib>Sametz, Wolfgang</creatorcontrib><creatorcontrib>Legat, Franz J.</creatorcontrib><creatorcontrib>Diethart, Sabine</creatorcontrib><creatorcontrib>Hammer, Susanne</creatorcontrib><creatorcontrib>Juan, Heinz</creatorcontrib><title>Effects of the non‐peptide B 2 antagonist FR173657 on kinin‐induced smooth muscle contraction and relaxation, vasoconstriction and prostaglandin release</title><title>British journal of pharmacology</title><description>The non‐peptide bradykinin (BK) antagonist (E)‐3‐(6‐acetamido‐3‐pyridyl)‐N‐[N‐[2,4‐dichloro‐3‐[(2‐ methyl‐8‐quinolinyl)oxymethyl]phenyl]‐N‐methylaminocarbonylmethyl]acrylamide (FR173657) was tested in intestinal, uterine, tracheal and vascular
in vitro
preparations. The investigation aimed at determining the antagonistic potency, duration of action, specificity for BK receptors and apparent mode of antagonistic action of FR173657.
Contractions of the isolated ileum of the guinea‐pig in response to BK were inhibited by FR173657 (10–300 n
M
) in a concentration‐dependent manner. The inhibition lasted for up to 90 min after wash‐out of FR173657. Cumulative concentration‐response curves to BK were shifted to the right with a concomitant decrease in the maximum effect. A p
K
B
value of 8.7 was determined. FR173657 had no effect on contractions induced by acetylcholine, histamine, 5‐hydroxytryptamine, substance P, angiotensin II or caerulein.
The concentration‐response curves for B
2
receptor‐mediated relaxations of the rat isolated duodenum induced by BK were shifted to the right together with a concomitant reduction of the maximum BK effect in the presence of FR173657 (10–300 n
M
). A p
K
B
of 9.0±0.2 was calculated. FR173657 had no effect on B
1
receptor‐mediated relaxations in response to des‐Arg
9
‐BK.
The concentration‐response curves for BK‐induced contractions of the rat isolated uterus were shifted to the right by FR173657 (3–300 n
M
) in a concentration‐dependent and parallel manner. The Schild plot for the inhibition caused by FR173657 had a slope of −0.98 indicating a competitive mode of antagonism. A pA
2
value of 9.1 was determined.
Contractions of the circular smooth muscles of the guinea‐pig isolated trachea in response to BK were concentration‐dependently inhibited by FR173657 (10–100 n
M
). An affinity estimate of 9.3 was calculated for FR173657. Contractions induced by acetylcholine and relaxations in response to isoprenaline remained completely unaffected by FR173657.
In the rabbit isolated perfused ear, BK (0.01–10 nmol) produced a dose‐dependent vasoconstriction. In the presence of 30 n
M
FR173657, the effects of BK were reduced by at least 60%, while FR173657 completely abolished the effects of all BK doses at 300 n
M
. FR173657 did not affect vasoconstriction induced by noradrenaline or angiotensin II.
The arterial injection of BK (10 nmol) into the rabbit isolated perfused ear caused an approximately three fold increase in the release of the prostaglandins E
2
and I
2
into the venous effluent. The BK‐stimulated prostaglandin release was completely abolished in the presence of FR173657 (300 n
M
) while the basal prostaglandin release was unchanged.
In summary, FR173657 was shown to be a highly potent and selective BK antagonist which was active on B
2
, but not B
1
, receptors. FR173657 was a competitive antagonist in the rat uterus but showed a deviation from competitive inhibition in the other preparations studied similar to other second generation peptide antagonists. The inhibitory action
in vitro
was long‐lasting, but was fully reversible.</description><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNpFkMFKAzEQhoMoWKtXz3kAd002zSY9ammrUBBEz0s2mbVZt8mySUVvPoIP4NP5JGaxIAzMDP_H_MOP0CUlOSVMXoc2r9s-J4JQyudHaEJnosw4k_QYTQghIqNUylN0FkJLSBIFn6DvZdOAjgH7BsctYOfdz-dXD320BvAtLrByUb14Z0PEq0cqWMkF9g6_WmdH1Dqz12Bw2Hkft3i3D7oDrL2Lg9LRJlI5gwfo1Lsa1yv8poJPeoiD_Qf6wYfk06XZuhEHFeAcnTSqC3Bx6FP0vFo-Le6yzcP6fnGzyTQt5zGTwAUvTSPKwsxlWWhGaklNISWpTapSzsSMc8ZrIUBToxgHAaRgTOuiaCSbovzvrk5fhAGaqh_sTg0fFSXVmG0V2iplWx2yZb9g8XJj</recordid><startdate>20090210</startdate><enddate>20090210</enddate><creator>Griesbacher, Thomas</creator><creator>Sametz, Wolfgang</creator><creator>Legat, Franz J.</creator><creator>Diethart, Sabine</creator><creator>Hammer, Susanne</creator><creator>Juan, Heinz</creator><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20090210</creationdate><title>Effects of the non‐peptide B 2 antagonist FR173657 on kinin‐induced smooth muscle contraction and relaxation, vasoconstriction and prostaglandin release</title><author>Griesbacher, Thomas ; Sametz, Wolfgang ; Legat, Franz J. ; Diethart, Sabine ; Hammer, Susanne ; Juan, Heinz</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c169t-8e5756df762d9862c30b81d2880bd0bd684745535b77ec1da35e7e0233cc22f83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Griesbacher, Thomas</creatorcontrib><creatorcontrib>Sametz, Wolfgang</creatorcontrib><creatorcontrib>Legat, Franz J.</creatorcontrib><creatorcontrib>Diethart, Sabine</creatorcontrib><creatorcontrib>Hammer, Susanne</creatorcontrib><creatorcontrib>Juan, Heinz</creatorcontrib><collection>CrossRef</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Griesbacher, Thomas</au><au>Sametz, Wolfgang</au><au>Legat, Franz J.</au><au>Diethart, Sabine</au><au>Hammer, Susanne</au><au>Juan, Heinz</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of the non‐peptide B 2 antagonist FR173657 on kinin‐induced smooth muscle contraction and relaxation, vasoconstriction and prostaglandin release</atitle><jtitle>British journal of pharmacology</jtitle><date>2009-02-10</date><risdate>2009</risdate><volume>121</volume><issue>3</issue><spage>469</spage><epage>476</epage><pages>469-476</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><abstract>The non‐peptide bradykinin (BK) antagonist (E)‐3‐(6‐acetamido‐3‐pyridyl)‐N‐[N‐[2,4‐dichloro‐3‐[(2‐ methyl‐8‐quinolinyl)oxymethyl]phenyl]‐N‐methylaminocarbonylmethyl]acrylamide (FR173657) was tested in intestinal, uterine, tracheal and vascular
in vitro
preparations. The investigation aimed at determining the antagonistic potency, duration of action, specificity for BK receptors and apparent mode of antagonistic action of FR173657.
Contractions of the isolated ileum of the guinea‐pig in response to BK were inhibited by FR173657 (10–300 n
M
) in a concentration‐dependent manner. The inhibition lasted for up to 90 min after wash‐out of FR173657. Cumulative concentration‐response curves to BK were shifted to the right with a concomitant decrease in the maximum effect. A p
K
B
value of 8.7 was determined. FR173657 had no effect on contractions induced by acetylcholine, histamine, 5‐hydroxytryptamine, substance P, angiotensin II or caerulein.
The concentration‐response curves for B
2
receptor‐mediated relaxations of the rat isolated duodenum induced by BK were shifted to the right together with a concomitant reduction of the maximum BK effect in the presence of FR173657 (10–300 n
M
). A p
K
B
of 9.0±0.2 was calculated. FR173657 had no effect on B
1
receptor‐mediated relaxations in response to des‐Arg
9
‐BK.
The concentration‐response curves for BK‐induced contractions of the rat isolated uterus were shifted to the right by FR173657 (3–300 n
M
) in a concentration‐dependent and parallel manner. The Schild plot for the inhibition caused by FR173657 had a slope of −0.98 indicating a competitive mode of antagonism. A pA
2
value of 9.1 was determined.
Contractions of the circular smooth muscles of the guinea‐pig isolated trachea in response to BK were concentration‐dependently inhibited by FR173657 (10–100 n
M
). An affinity estimate of 9.3 was calculated for FR173657. Contractions induced by acetylcholine and relaxations in response to isoprenaline remained completely unaffected by FR173657.
In the rabbit isolated perfused ear, BK (0.01–10 nmol) produced a dose‐dependent vasoconstriction. In the presence of 30 n
M
FR173657, the effects of BK were reduced by at least 60%, while FR173657 completely abolished the effects of all BK doses at 300 n
M
. FR173657 did not affect vasoconstriction induced by noradrenaline or angiotensin II.
The arterial injection of BK (10 nmol) into the rabbit isolated perfused ear caused an approximately three fold increase in the release of the prostaglandins E
2
and I
2
into the venous effluent. The BK‐stimulated prostaglandin release was completely abolished in the presence of FR173657 (300 n
M
) while the basal prostaglandin release was unchanged.
In summary, FR173657 was shown to be a highly potent and selective BK antagonist which was active on B
2
, but not B
1
, receptors. FR173657 was a competitive antagonist in the rat uterus but showed a deviation from competitive inhibition in the other preparations studied similar to other second generation peptide antagonists. The inhibitory action
in vitro
was long‐lasting, but was fully reversible.</abstract><doi>10.1038/sj.bjp.0701159</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| title | Effects of the non‐peptide B 2 antagonist FR173657 on kinin‐induced smooth muscle contraction and relaxation, vasoconstriction and prostaglandin release |
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