Anti-platelet activity of KR-32560, a novel sodium/hydrogen exchanger-1 inhibitor
We investigated the anti-platelet effect of a newly synthesized guanidine derivative KR-32560, a sodium/hydrogen exchanger-1 (NHE-1) inhibitor, together with the elucidation of the possible mode of action. KR-32560 concentration dependently inhibited the aggregation of washed rabbit platelets induce...
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| Veröffentlicht in: | Pharmacological research 2006-03, Vol.53 (3), p.265-270 |
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| creator | Lee, Kyung-Sup Jin, Yong-Ri Lee, Jung-Jin Lim, Yong Son, Dong-Ju Lee, Chong-Kil Yi, Kyu-Yang Yoo, Sung-Eun Shin, Hwa-Sup Yun, Yeo-Pyo |
| description | We investigated the anti-platelet effect of a newly synthesized guanidine derivative KR-32560, a sodium/hydrogen exchanger-1 (NHE-1) inhibitor, together with the elucidation of the possible mode of action. KR-32560 concentration dependently inhibited the aggregation of washed rabbit platelets induced by collagen (10
μg
mL
−1) and arachidonic acid (AA; 100
μM), with IC
50 values of 25 and 46
μM, respectively. Whereas, KR-32560 showed weaker potency against aggregation induced by thrombin (0.05 U
mL
−1) and U46619 (1
μM), and had no effect on thapsigargin (0.5
μM)- or A23187 (5
μM)-induced platelet aggregation up to 50
μM. KR-32560 inhibited the collagen-induced [
3H]AA liberation in a concentration-dependent manner. In addition, KR-32560 significantly suppressed TXB
2 formation in AA-exposed platelets, but had no effect on production of PGD
2, indicating an inhibitory effect on TXA
2 synthase. This finding was supported by a TXA
2 synthase assay that KR-32560 inhibited the conversion of PGH
2 into TXB
2 with a similar magnitude to suppression of TXB
2 formation. Furthermore, KR-32560 significantly inhibited the collagen-induced [Ca
2+]
i mobilization and serotonin secretion. Taken together, these observations suggest that the anti-platelet activity of KR-32560 may be mediated by the inhibition of cytoplasmic Ca
2+ mobilization and AA liberation. |
| doi_str_mv | 10.1016/j.phrs.2005.12.003 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_67671598</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1043661805002215</els_id><sourcerecordid>67671598</sourcerecordid><originalsourceid>FETCH-LOGICAL-c354t-4a62e6d352bce1e5f0c48ae75219c1dc62e5d70ac1b61ef5ebc1f79b6d3925183</originalsourceid><addsrcrecordid>eNp9kMFO4zAQhi3EagvsvgAHlBMnEmac2EkkLgixC1okBGLPluNMWldpXGy3om9PolbixmlGmu__pfkYO0fIEFBeL7P1woeMA4gMeQaQH7EThFqmiJU8nvYiT6XEasZOQ1gCQF0g_GQzlAWHuoIT9nI7RJuuex2pp5hoE-3Wxl3iuuTfa5pzIeEq0cngttQnwbV2s7pe7Frv5jQk9GEWepiTTzGxw8I2Njr_i_3odB_o92Gesf9_7t_uHtKn57-Pd7dPqclFEdNCS06yzQVvDCGJDkxRaSoFx9pga8araEvQBhuJ1AlqDHZl3YyRmgus8jN2ue9de_e-oRDVygZDfa8HcpugZClLFPUE8j1ovAvBU6fW3q603ykENYlUSzWJVJNIhVyNIsfQxaF906yo_YoczI3AzR6g8cetJa-CsTQYaq0nE1Xr7Hf9n69ug8Q</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>67671598</pqid></control><display><type>article</type><title>Anti-platelet activity of KR-32560, a novel sodium/hydrogen exchanger-1 inhibitor</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals Complete</source><creator>Lee, Kyung-Sup ; Jin, Yong-Ri ; Lee, Jung-Jin ; Lim, Yong ; Son, Dong-Ju ; Lee, Chong-Kil ; Yi, Kyu-Yang ; Yoo, Sung-Eun ; Shin, Hwa-Sup ; Yun, Yeo-Pyo</creator><creatorcontrib>Lee, Kyung-Sup ; Jin, Yong-Ri ; Lee, Jung-Jin ; Lim, Yong ; Son, Dong-Ju ; Lee, Chong-Kil ; Yi, Kyu-Yang ; Yoo, Sung-Eun ; Shin, Hwa-Sup ; Yun, Yeo-Pyo</creatorcontrib><description>We investigated the anti-platelet effect of a newly synthesized guanidine derivative KR-32560, a sodium/hydrogen exchanger-1 (NHE-1) inhibitor, together with the elucidation of the possible mode of action. KR-32560 concentration dependently inhibited the aggregation of washed rabbit platelets induced by collagen (10
μg
mL
−1) and arachidonic acid (AA; 100
μM), with IC
50 values of 25 and 46
μM, respectively. Whereas, KR-32560 showed weaker potency against aggregation induced by thrombin (0.05 U
mL
−1) and U46619 (1
μM), and had no effect on thapsigargin (0.5
μM)- or A23187 (5
μM)-induced platelet aggregation up to 50
μM. KR-32560 inhibited the collagen-induced [
3H]AA liberation in a concentration-dependent manner. In addition, KR-32560 significantly suppressed TXB
2 formation in AA-exposed platelets, but had no effect on production of PGD
2, indicating an inhibitory effect on TXA
2 synthase. This finding was supported by a TXA
2 synthase assay that KR-32560 inhibited the conversion of PGH
2 into TXB
2 with a similar magnitude to suppression of TXB
2 formation. Furthermore, KR-32560 significantly inhibited the collagen-induced [Ca
2+]
i mobilization and serotonin secretion. Taken together, these observations suggest that the anti-platelet activity of KR-32560 may be mediated by the inhibition of cytoplasmic Ca
2+ mobilization and AA liberation.</description><identifier>ISSN: 1043-6618</identifier><identifier>EISSN: 1096-1186</identifier><identifier>DOI: 10.1016/j.phrs.2005.12.003</identifier><identifier>PMID: 16420980</identifier><language>eng</language><publisher>Netherlands: Elsevier Ltd</publisher><subject>[Ca 2+] i mobilization ; Animals ; Arachidonic Acid - metabolism ; Arachidonic Acid - pharmacology ; Arachidonic acid liberation ; Blood Platelets - drug effects ; Blood Platelets - enzymology ; Calcium - metabolism ; Collagen - pharmacology ; Dose-Response Relationship, Drug ; Guanidines - pharmacology ; In Vitro Techniques ; KR-32560 ; Male ; Platelet Aggregation ; Platelet Aggregation Inhibitors - pharmacology ; Rabbits ; Serotonin - metabolism ; Sodium-Hydrogen Exchangers - antagonists & inhibitors ; Sodium–hydrogen exchanger-1 ; Thromboxane B2 - metabolism ; Thromboxane-A Synthase - antagonists & inhibitors ; Thromboxane-A Synthase - metabolism</subject><ispartof>Pharmacological research, 2006-03, Vol.53 (3), p.265-270</ispartof><rights>2005 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-4a62e6d352bce1e5f0c48ae75219c1dc62e5d70ac1b61ef5ebc1f79b6d3925183</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.phrs.2005.12.003$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16420980$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Kyung-Sup</creatorcontrib><creatorcontrib>Jin, Yong-Ri</creatorcontrib><creatorcontrib>Lee, Jung-Jin</creatorcontrib><creatorcontrib>Lim, Yong</creatorcontrib><creatorcontrib>Son, Dong-Ju</creatorcontrib><creatorcontrib>Lee, Chong-Kil</creatorcontrib><creatorcontrib>Yi, Kyu-Yang</creatorcontrib><creatorcontrib>Yoo, Sung-Eun</creatorcontrib><creatorcontrib>Shin, Hwa-Sup</creatorcontrib><creatorcontrib>Yun, Yeo-Pyo</creatorcontrib><title>Anti-platelet activity of KR-32560, a novel sodium/hydrogen exchanger-1 inhibitor</title><title>Pharmacological research</title><addtitle>Pharmacol Res</addtitle><description>We investigated the anti-platelet effect of a newly synthesized guanidine derivative KR-32560, a sodium/hydrogen exchanger-1 (NHE-1) inhibitor, together with the elucidation of the possible mode of action. KR-32560 concentration dependently inhibited the aggregation of washed rabbit platelets induced by collagen (10
μg
mL
−1) and arachidonic acid (AA; 100
μM), with IC
50 values of 25 and 46
μM, respectively. Whereas, KR-32560 showed weaker potency against aggregation induced by thrombin (0.05 U
mL
−1) and U46619 (1
μM), and had no effect on thapsigargin (0.5
μM)- or A23187 (5
μM)-induced platelet aggregation up to 50
μM. KR-32560 inhibited the collagen-induced [
3H]AA liberation in a concentration-dependent manner. In addition, KR-32560 significantly suppressed TXB
2 formation in AA-exposed platelets, but had no effect on production of PGD
2, indicating an inhibitory effect on TXA
2 synthase. This finding was supported by a TXA
2 synthase assay that KR-32560 inhibited the conversion of PGH
2 into TXB
2 with a similar magnitude to suppression of TXB
2 formation. Furthermore, KR-32560 significantly inhibited the collagen-induced [Ca
2+]
i mobilization and serotonin secretion. Taken together, these observations suggest that the anti-platelet activity of KR-32560 may be mediated by the inhibition of cytoplasmic Ca
2+ mobilization and AA liberation.</description><subject>[Ca 2+] i mobilization</subject><subject>Animals</subject><subject>Arachidonic Acid - metabolism</subject><subject>Arachidonic Acid - pharmacology</subject><subject>Arachidonic acid liberation</subject><subject>Blood Platelets - drug effects</subject><subject>Blood Platelets - enzymology</subject><subject>Calcium - metabolism</subject><subject>Collagen - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Guanidines - pharmacology</subject><subject>In Vitro Techniques</subject><subject>KR-32560</subject><subject>Male</subject><subject>Platelet Aggregation</subject><subject>Platelet Aggregation Inhibitors - pharmacology</subject><subject>Rabbits</subject><subject>Serotonin - metabolism</subject><subject>Sodium-Hydrogen Exchangers - antagonists & inhibitors</subject><subject>Sodium–hydrogen exchanger-1</subject><subject>Thromboxane B2 - metabolism</subject><subject>Thromboxane-A Synthase - antagonists & inhibitors</subject><subject>Thromboxane-A Synthase - metabolism</subject><issn>1043-6618</issn><issn>1096-1186</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFO4zAQhi3EagvsvgAHlBMnEmac2EkkLgixC1okBGLPluNMWldpXGy3om9PolbixmlGmu__pfkYO0fIEFBeL7P1woeMA4gMeQaQH7EThFqmiJU8nvYiT6XEasZOQ1gCQF0g_GQzlAWHuoIT9nI7RJuuex2pp5hoE-3Wxl3iuuTfa5pzIeEq0cngttQnwbV2s7pe7Frv5jQk9GEWepiTTzGxw8I2Njr_i_3odB_o92Gesf9_7t_uHtKn57-Pd7dPqclFEdNCS06yzQVvDCGJDkxRaSoFx9pga8araEvQBhuJ1AlqDHZl3YyRmgus8jN2ue9de_e-oRDVygZDfa8HcpugZClLFPUE8j1ovAvBU6fW3q603ykENYlUSzWJVJNIhVyNIsfQxaF906yo_YoczI3AzR6g8cetJa-CsTQYaq0nE1Xr7Hf9n69ug8Q</recordid><startdate>20060301</startdate><enddate>20060301</enddate><creator>Lee, Kyung-Sup</creator><creator>Jin, Yong-Ri</creator><creator>Lee, Jung-Jin</creator><creator>Lim, Yong</creator><creator>Son, Dong-Ju</creator><creator>Lee, Chong-Kil</creator><creator>Yi, Kyu-Yang</creator><creator>Yoo, Sung-Eun</creator><creator>Shin, Hwa-Sup</creator><creator>Yun, Yeo-Pyo</creator><general>Elsevier Ltd</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></search><sort><creationdate>20060301</creationdate><title>Anti-platelet activity of KR-32560, a novel sodium/hydrogen exchanger-1 inhibitor</title><author>Lee, Kyung-Sup ; Jin, Yong-Ri ; Lee, Jung-Jin ; Lim, Yong ; Son, Dong-Ju ; Lee, Chong-Kil ; Yi, Kyu-Yang ; Yoo, Sung-Eun ; Shin, Hwa-Sup ; Yun, Yeo-Pyo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-4a62e6d352bce1e5f0c48ae75219c1dc62e5d70ac1b61ef5ebc1f79b6d3925183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>[Ca 2+] i mobilization</topic><topic>Animals</topic><topic>Arachidonic Acid - metabolism</topic><topic>Arachidonic Acid - pharmacology</topic><topic>Arachidonic acid liberation</topic><topic>Blood Platelets - drug effects</topic><topic>Blood Platelets - enzymology</topic><topic>Calcium - metabolism</topic><topic>Collagen - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Guanidines - pharmacology</topic><topic>In Vitro Techniques</topic><topic>KR-32560</topic><topic>Male</topic><topic>Platelet Aggregation</topic><topic>Platelet Aggregation Inhibitors - pharmacology</topic><topic>Rabbits</topic><topic>Serotonin - metabolism</topic><topic>Sodium-Hydrogen Exchangers - antagonists & inhibitors</topic><topic>Sodium–hydrogen exchanger-1</topic><topic>Thromboxane B2 - metabolism</topic><topic>Thromboxane-A Synthase - antagonists & inhibitors</topic><topic>Thromboxane-A Synthase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Kyung-Sup</creatorcontrib><creatorcontrib>Jin, Yong-Ri</creatorcontrib><creatorcontrib>Lee, Jung-Jin</creatorcontrib><creatorcontrib>Lim, Yong</creatorcontrib><creatorcontrib>Son, Dong-Ju</creatorcontrib><creatorcontrib>Lee, Chong-Kil</creatorcontrib><creatorcontrib>Yi, Kyu-Yang</creatorcontrib><creatorcontrib>Yoo, Sung-Eun</creatorcontrib><creatorcontrib>Shin, Hwa-Sup</creatorcontrib><creatorcontrib>Yun, Yeo-Pyo</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>Pharmacological research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Kyung-Sup</au><au>Jin, Yong-Ri</au><au>Lee, Jung-Jin</au><au>Lim, Yong</au><au>Son, Dong-Ju</au><au>Lee, Chong-Kil</au><au>Yi, Kyu-Yang</au><au>Yoo, Sung-Eun</au><au>Shin, Hwa-Sup</au><au>Yun, Yeo-Pyo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anti-platelet activity of KR-32560, a novel sodium/hydrogen exchanger-1 inhibitor</atitle><jtitle>Pharmacological research</jtitle><addtitle>Pharmacol Res</addtitle><date>2006-03-01</date><risdate>2006</risdate><volume>53</volume><issue>3</issue><spage>265</spage><epage>270</epage><pages>265-270</pages><issn>1043-6618</issn><eissn>1096-1186</eissn><abstract>We investigated the anti-platelet effect of a newly synthesized guanidine derivative KR-32560, a sodium/hydrogen exchanger-1 (NHE-1) inhibitor, together with the elucidation of the possible mode of action. KR-32560 concentration dependently inhibited the aggregation of washed rabbit platelets induced by collagen (10
μg
mL
−1) and arachidonic acid (AA; 100
μM), with IC
50 values of 25 and 46
μM, respectively. Whereas, KR-32560 showed weaker potency against aggregation induced by thrombin (0.05 U
mL
−1) and U46619 (1
μM), and had no effect on thapsigargin (0.5
μM)- or A23187 (5
μM)-induced platelet aggregation up to 50
μM. KR-32560 inhibited the collagen-induced [
3H]AA liberation in a concentration-dependent manner. In addition, KR-32560 significantly suppressed TXB
2 formation in AA-exposed platelets, but had no effect on production of PGD
2, indicating an inhibitory effect on TXA
2 synthase. This finding was supported by a TXA
2 synthase assay that KR-32560 inhibited the conversion of PGH
2 into TXB
2 with a similar magnitude to suppression of TXB
2 formation. Furthermore, KR-32560 significantly inhibited the collagen-induced [Ca
2+]
i mobilization and serotonin secretion. Taken together, these observations suggest that the anti-platelet activity of KR-32560 may be mediated by the inhibition of cytoplasmic Ca
2+ mobilization and AA liberation.</abstract><cop>Netherlands</cop><pub>Elsevier Ltd</pub><pmid>16420980</pmid><doi>10.1016/j.phrs.2005.12.003</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1043-6618 |
| ispartof | Pharmacological research, 2006-03, Vol.53 (3), p.265-270 |
| issn | 1043-6618 1096-1186 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | [Ca 2+] i mobilization Animals Arachidonic Acid - metabolism Arachidonic Acid - pharmacology Arachidonic acid liberation Blood Platelets - drug effects Blood Platelets - enzymology Calcium - metabolism Collagen - pharmacology Dose-Response Relationship, Drug Guanidines - pharmacology In Vitro Techniques KR-32560 Male Platelet Aggregation Platelet Aggregation Inhibitors - pharmacology Rabbits Serotonin - metabolism Sodium-Hydrogen Exchangers - antagonists & inhibitors Sodium–hydrogen exchanger-1 Thromboxane B2 - metabolism Thromboxane-A Synthase - antagonists & inhibitors Thromboxane-A Synthase - metabolism |
| title | Anti-platelet activity of KR-32560, a novel sodium/hydrogen exchanger-1 inhibitor |
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