Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice
Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increas...
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| Veröffentlicht in: | American journal of physiology. Heart and circulatory physiology 2021-08, Vol.321 (2), p.H400-H411 |
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| container_title | American journal of physiology. Heart and circulatory physiology |
| container_volume | 321 |
| creator | Dufu, Kobina Williams, Alexander T. Muller, Cynthia R. Walser, Cynthia M. Lucas, Alfredo Eaker, Allyn M. Alt, Carsten Cathers, Brian E. Oksenberg, Donna Cabrales, Pedro |
| description | Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen.
Therapeutic agents that increase the Hb affinity for oxygen (O
2
) could, in theory, lead to decreased O
2
release from Hb and impose a hypoxic risk to tissues. In this study, GBT1118, an allosteric modifier of Hb affinity for O
2
, was used to assess the impact of increasing Hb affinity for O
2
on brain tissue oxygenation, blood pressure, heart rate, O
2
delivery, and tolerance to hypoxia in Townes transgenic sickle cell disease (SCD) mice. Brain oxygenation and O
2
delivery were studied during normoxia and severe hypoxic challenges. Chronic treatment with GBT1118 increased Hb affinity for O
2
, reducing the Po
2
for 50% HbO
2
saturation (P50) in SCD mice from 31 mmHg to 18 mmHg. This treatment significantly reduced anemia, increasing hematocrit by 33%, improved cardiac output (CO), and O
2
delivery and extraction. Chronically increasing Hb affinity for O
2
with GBT1118 preserved cortical O
2
tension during normoxia, improved cortical O
2
tension during hypoxia, and increased tolerance to severe hypoxia in SCD mice. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O
2
and consequently reducing sickling of RBCs in blood during hypoxia in SCD.
NEW & NOTEWORTHY Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen. |
| doi_str_mv | 10.1152/ajpheart.00048.2021 |
| format | Article |
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Therapeutic agents that increase the Hb affinity for oxygen (O
2
) could, in theory, lead to decreased O
2
release from Hb and impose a hypoxic risk to tissues. In this study, GBT1118, an allosteric modifier of Hb affinity for O
2
, was used to assess the impact of increasing Hb affinity for O
2
on brain tissue oxygenation, blood pressure, heart rate, O
2
delivery, and tolerance to hypoxia in Townes transgenic sickle cell disease (SCD) mice. Brain oxygenation and O
2
delivery were studied during normoxia and severe hypoxic challenges. Chronic treatment with GBT1118 increased Hb affinity for O
2
, reducing the Po
2
for 50% HbO
2
saturation (P50) in SCD mice from 31 mmHg to 18 mmHg. This treatment significantly reduced anemia, increasing hematocrit by 33%, improved cardiac output (CO), and O
2
delivery and extraction. Chronically increasing Hb affinity for O
2
with GBT1118 preserved cortical O
2
tension during normoxia, improved cortical O
2
tension during hypoxia, and increased tolerance to severe hypoxia in SCD mice. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O
2
and consequently reducing sickling of RBCs in blood during hypoxia in SCD.
NEW & NOTEWORTHY Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen.</description><identifier>ISSN: 0363-6135</identifier><identifier>EISSN: 1522-1539</identifier><identifier>DOI: 10.1152/ajpheart.00048.2021</identifier><identifier>PMID: 34213392</identifier><language>eng</language><publisher>Bethesda: American Physiological Society</publisher><subject>Affinity ; Allosteric properties ; Anemia ; Blood pressure ; Brain ; Cardiac output ; Chemical compounds ; Heart rate ; Hematocrit ; Hemoglobin ; Hypoxia ; Oxygen ; Oxygenation ; Pharmacology ; Sickle cell disease</subject><ispartof>American journal of physiology. Heart and circulatory physiology, 2021-08, Vol.321 (2), p.H400-H411</ispartof><rights>Copyright American Physiological Society Aug 2021</rights><rights>Copyright © 2021 the American Physiological Society 2021 American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c410t-bb8ba92123d6cae2b55d2627cc01dce4842e71374eafe9e6400c40646c6566373</citedby><cites>FETCH-LOGICAL-c410t-bb8ba92123d6cae2b55d2627cc01dce4842e71374eafe9e6400c40646c6566373</cites><orcidid>0000-0002-8794-2839 ; 0000-0001-5506-7534 ; 0000-0003-2150-9263</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3039,27924,27925</link.rule.ids></links><search><creatorcontrib>Dufu, Kobina</creatorcontrib><creatorcontrib>Williams, Alexander T.</creatorcontrib><creatorcontrib>Muller, Cynthia R.</creatorcontrib><creatorcontrib>Walser, Cynthia M.</creatorcontrib><creatorcontrib>Lucas, Alfredo</creatorcontrib><creatorcontrib>Eaker, Allyn M.</creatorcontrib><creatorcontrib>Alt, Carsten</creatorcontrib><creatorcontrib>Cathers, Brian E.</creatorcontrib><creatorcontrib>Oksenberg, Donna</creatorcontrib><creatorcontrib>Cabrales, Pedro</creatorcontrib><title>Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice</title><title>American journal of physiology. Heart and circulatory physiology</title><description>Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen.
Therapeutic agents that increase the Hb affinity for oxygen (O
2
) could, in theory, lead to decreased O
2
release from Hb and impose a hypoxic risk to tissues. In this study, GBT1118, an allosteric modifier of Hb affinity for O
2
, was used to assess the impact of increasing Hb affinity for O
2
on brain tissue oxygenation, blood pressure, heart rate, O
2
delivery, and tolerance to hypoxia in Townes transgenic sickle cell disease (SCD) mice. Brain oxygenation and O
2
delivery were studied during normoxia and severe hypoxic challenges. Chronic treatment with GBT1118 increased Hb affinity for O
2
, reducing the Po
2
for 50% HbO
2
saturation (P50) in SCD mice from 31 mmHg to 18 mmHg. This treatment significantly reduced anemia, increasing hematocrit by 33%, improved cardiac output (CO), and O
2
delivery and extraction. Chronically increasing Hb affinity for O
2
with GBT1118 preserved cortical O
2
tension during normoxia, improved cortical O
2
tension during hypoxia, and increased tolerance to severe hypoxia in SCD mice. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O
2
and consequently reducing sickling of RBCs in blood during hypoxia in SCD.
NEW & NOTEWORTHY Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen.</description><subject>Affinity</subject><subject>Allosteric properties</subject><subject>Anemia</subject><subject>Blood pressure</subject><subject>Brain</subject><subject>Cardiac output</subject><subject>Chemical compounds</subject><subject>Heart rate</subject><subject>Hematocrit</subject><subject>Hemoglobin</subject><subject>Hypoxia</subject><subject>Oxygen</subject><subject>Oxygenation</subject><subject>Pharmacology</subject><subject>Sickle cell disease</subject><issn>0363-6135</issn><issn>1522-1539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNpVkbtOwzAUhi0EgnJ5AhZLzCm-J12QoIKCVImlzJbjnDQuSRzstLRvTwoFiekM_-1IH0LXlIwplezWrLoKTOjHhBCRjRlh9AiNBoUlVPLJMRoRrniiKJdn6DzG1eCTqeKn6IwLRjmfsBEqXlobwEQocAWNX9Y-dy02Zela1-9w6QP2290SWvzp-grPHhaU0gy7pgt-AxFXu85vncG9ryGY1gIe4tHZ9xqwhbrGjbNwiU5KU0e4OtwL9Pb0uJg-J_PX2cv0fp5YQUmf5HmWmwmjjBfKGmC5lAVTLLWW0MKCyASDlPJUgClhAkoQYgVRQlklleIpv0B3P73dOm9giLR9MLXugmtM2GlvnP6vtK7SS7_R2bBPGRkKbg4FwX-sIfZ65dehHX7WTKaEcckzObj4j8sGH2OA8m-BEr1Ho3_R6G80eo-GfwFdi4OQ</recordid><startdate>20210801</startdate><enddate>20210801</enddate><creator>Dufu, Kobina</creator><creator>Williams, Alexander T.</creator><creator>Muller, Cynthia R.</creator><creator>Walser, Cynthia M.</creator><creator>Lucas, Alfredo</creator><creator>Eaker, Allyn M.</creator><creator>Alt, Carsten</creator><creator>Cathers, Brian E.</creator><creator>Oksenberg, Donna</creator><creator>Cabrales, Pedro</creator><general>American Physiological Society</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TS</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8794-2839</orcidid><orcidid>https://orcid.org/0000-0001-5506-7534</orcidid><orcidid>https://orcid.org/0000-0003-2150-9263</orcidid></search><sort><creationdate>20210801</creationdate><title>Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice</title><author>Dufu, Kobina ; Williams, Alexander T. ; Muller, Cynthia R. ; Walser, Cynthia M. ; Lucas, Alfredo ; Eaker, Allyn M. ; Alt, Carsten ; Cathers, Brian E. ; Oksenberg, Donna ; Cabrales, Pedro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c410t-bb8ba92123d6cae2b55d2627cc01dce4842e71374eafe9e6400c40646c6566373</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Affinity</topic><topic>Allosteric properties</topic><topic>Anemia</topic><topic>Blood pressure</topic><topic>Brain</topic><topic>Cardiac output</topic><topic>Chemical compounds</topic><topic>Heart rate</topic><topic>Hematocrit</topic><topic>Hemoglobin</topic><topic>Hypoxia</topic><topic>Oxygen</topic><topic>Oxygenation</topic><topic>Pharmacology</topic><topic>Sickle cell disease</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dufu, Kobina</creatorcontrib><creatorcontrib>Williams, Alexander T.</creatorcontrib><creatorcontrib>Muller, Cynthia R.</creatorcontrib><creatorcontrib>Walser, Cynthia M.</creatorcontrib><creatorcontrib>Lucas, Alfredo</creatorcontrib><creatorcontrib>Eaker, Allyn M.</creatorcontrib><creatorcontrib>Alt, Carsten</creatorcontrib><creatorcontrib>Cathers, Brian E.</creatorcontrib><creatorcontrib>Oksenberg, Donna</creatorcontrib><creatorcontrib>Cabrales, Pedro</creatorcontrib><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Physical Education Index</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of physiology. Heart and circulatory physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dufu, Kobina</au><au>Williams, Alexander T.</au><au>Muller, Cynthia R.</au><au>Walser, Cynthia M.</au><au>Lucas, Alfredo</au><au>Eaker, Allyn M.</au><au>Alt, Carsten</au><au>Cathers, Brian E.</au><au>Oksenberg, Donna</au><au>Cabrales, Pedro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice</atitle><jtitle>American journal of physiology. Heart and circulatory physiology</jtitle><date>2021-08-01</date><risdate>2021</risdate><volume>321</volume><issue>2</issue><spage>H400</spage><epage>H411</epage><pages>H400-H411</pages><issn>0363-6135</issn><eissn>1522-1539</eissn><abstract>Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen.
Therapeutic agents that increase the Hb affinity for oxygen (O
2
) could, in theory, lead to decreased O
2
release from Hb and impose a hypoxic risk to tissues. In this study, GBT1118, an allosteric modifier of Hb affinity for O
2
, was used to assess the impact of increasing Hb affinity for O
2
on brain tissue oxygenation, blood pressure, heart rate, O
2
delivery, and tolerance to hypoxia in Townes transgenic sickle cell disease (SCD) mice. Brain oxygenation and O
2
delivery were studied during normoxia and severe hypoxic challenges. Chronic treatment with GBT1118 increased Hb affinity for O
2
, reducing the Po
2
for 50% HbO
2
saturation (P50) in SCD mice from 31 mmHg to 18 mmHg. This treatment significantly reduced anemia, increasing hematocrit by 33%, improved cardiac output (CO), and O
2
delivery and extraction. Chronically increasing Hb affinity for O
2
with GBT1118 preserved cortical O
2
tension during normoxia, improved cortical O
2
tension during hypoxia, and increased tolerance to severe hypoxia in SCD mice. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O
2
and consequently reducing sickling of RBCs in blood during hypoxia in SCD.
NEW & NOTEWORTHY Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen.</abstract><cop>Bethesda</cop><pub>American Physiological Society</pub><pmid>34213392</pmid><doi>10.1152/ajpheart.00048.2021</doi><orcidid>https://orcid.org/0000-0002-8794-2839</orcidid><orcidid>https://orcid.org/0000-0001-5506-7534</orcidid><orcidid>https://orcid.org/0000-0003-2150-9263</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0363-6135 |
| ispartof | American journal of physiology. Heart and circulatory physiology, 2021-08, Vol.321 (2), p.H400-H411 |
| issn | 0363-6135 1522-1539 |
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| source | American Physiological Society; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Affinity Allosteric properties Anemia Blood pressure Brain Cardiac output Chemical compounds Heart rate Hematocrit Hemoglobin Hypoxia Oxygen Oxygenation Pharmacology Sickle cell disease |
| title | Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice |
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