Cardioprotective effects of novel tetrahydroisoquinoline analogs of nitrobenzylmercaptopurine riboside in an isolated perfused rat heart model of acute myocardial infarction
1 Department of Pharmaceutical Sciences, College of Pharmacy, and 2 Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee Submitted 10 November 2005 ; accepted in final form 2 February 2007 We have investigated the cardioprotective effects o...
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| Veröffentlicht in: | American journal of physiology. Heart and circulatory physiology 2007-06, Vol.292 (6), p.H2921-H2926 |
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| container_title | American journal of physiology. Heart and circulatory physiology |
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| creator | Zhu, Z Hofmann, P. A Buolamwini, J. K |
| description | 1 Department of Pharmaceutical Sciences, College of Pharmacy, and 2 Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
Submitted 10 November 2005
; accepted in final form 2 February 2007
We have investigated the cardioprotective effects of novel tetrahydroisoquinoline nitrobenzylmercaptopurine riboside (NBMPR) analog nucleoside transport (NT) inhibitors, compounds 2 and 4, in isolated perfused rat hearts. Langendorff-perfused heart preparations were subjected to 10 min of treatment with compound 2, compound 4, or vehicle (control) followed by 30 min of global ischemia and 120 min of reperfusion. For determination of infarct size, reperfusion time was 180 min. At 1 µM, compounds 2 and 4 provided excellent cardioprotection, with left ventricular developed pressure (LVDP) recovery and end-diastolic pressure (EDP) increase of 82.9 ± 4.0% ( P < 0.001) and 14.1 ± 2.0 mmHg ( P < 0.03) for compound 2-treated hearts and 79.2 ± 5.9% ( P < 0.002) and 7.5 ± 2.7 mmHg ( P < 0.01) for compound 4-treated hearts compared with 41.6 ± 5.2% and 42.5 ± 6.5 mmHg for control hearts. LVDP recovery and EDP increase were 64.1 ± 4.2% and 29.1 ± 2.5 mmHg for hearts treated with 1 µM NBMPR. Compound 4 was the best cardioprotective agent, affording significant cardioprotection, even at 0.1 µM, with LVDP recovery and EDP increase of 76.0 ± 4.9% ( P < 0.003) and 14.1 ± 1.0 mmHg ( P < 0.03). At 1 µM, compound 4 and NBMPR reduced infarct size, with infarct area-to-total risk area ratios of 29.13 ± 3.17 ( P < 0.001) for compound 4 and 37.5 ± 3.42 ( P < 0.01) for NBMPR vs. 51.08 ± 5.06% for control hearts. Infarct size was more effectively reduced by compound 4 than by NBMPR ( P < 0.02). These new tetrahydroisoquinoline NBMPR analogs are not only potent cardioprotective agents but are, also, more effective than NBMPR in this model.
cardioprotection; nucleoside transport inhibitors; left ventricular developed pressure; end-diastolic pressure; ischemia; reperfusion; adenosine potentiation; infarct size reduction
Address for reprint requests and other correspondence: J. K. Buolamwini, Dept. Pharmaceutical Sciences, College of Pharmacy, Univ. of Tennessee Health Science Center, 847 Monroe Ave., Suite 327, Memphis, TN 38163 (e-mail: jbuolamwini{at}utmem.edu ) |
| doi_str_mv | 10.1152/ajpheart.01191.2005 |
| format | Article |
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Submitted 10 November 2005
; accepted in final form 2 February 2007
We have investigated the cardioprotective effects of novel tetrahydroisoquinoline nitrobenzylmercaptopurine riboside (NBMPR) analog nucleoside transport (NT) inhibitors, compounds 2 and 4, in isolated perfused rat hearts. Langendorff-perfused heart preparations were subjected to 10 min of treatment with compound 2, compound 4, or vehicle (control) followed by 30 min of global ischemia and 120 min of reperfusion. For determination of infarct size, reperfusion time was 180 min. At 1 µM, compounds 2 and 4 provided excellent cardioprotection, with left ventricular developed pressure (LVDP) recovery and end-diastolic pressure (EDP) increase of 82.9 ± 4.0% ( P < 0.001) and 14.1 ± 2.0 mmHg ( P < 0.03) for compound 2-treated hearts and 79.2 ± 5.9% ( P < 0.002) and 7.5 ± 2.7 mmHg ( P < 0.01) for compound 4-treated hearts compared with 41.6 ± 5.2% and 42.5 ± 6.5 mmHg for control hearts. LVDP recovery and EDP increase were 64.1 ± 4.2% and 29.1 ± 2.5 mmHg for hearts treated with 1 µM NBMPR. Compound 4 was the best cardioprotective agent, affording significant cardioprotection, even at 0.1 µM, with LVDP recovery and EDP increase of 76.0 ± 4.9% ( P < 0.003) and 14.1 ± 1.0 mmHg ( P < 0.03). At 1 µM, compound 4 and NBMPR reduced infarct size, with infarct area-to-total risk area ratios of 29.13 ± 3.17 ( P < 0.001) for compound 4 and 37.5 ± 3.42 ( P < 0.01) for NBMPR vs. 51.08 ± 5.06% for control hearts. Infarct size was more effectively reduced by compound 4 than by NBMPR ( P < 0.02). These new tetrahydroisoquinoline NBMPR analogs are not only potent cardioprotective agents but are, also, more effective than NBMPR in this model.
cardioprotection; nucleoside transport inhibitors; left ventricular developed pressure; end-diastolic pressure; ischemia; reperfusion; adenosine potentiation; infarct size reduction
Address for reprint requests and other correspondence: J. K. Buolamwini, Dept. Pharmaceutical Sciences, College of Pharmacy, Univ. of Tennessee Health Science Center, 847 Monroe Ave., Suite 327, Memphis, TN 38163 (e-mail: jbuolamwini{at}utmem.edu )]]></description><identifier>ISSN: 0363-6135</identifier><identifier>EISSN: 1522-1539</identifier><identifier>DOI: 10.1152/ajpheart.01191.2005</identifier><identifier>PMID: 17293492</identifier><identifier>CODEN: AJPPDI</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animals ; Cardiology ; Cardiotonic Agents - pharmacology ; Cardiotonic Agents - therapeutic use ; Chemical compounds ; Clinical outcomes ; Dose-Response Relationship, Drug ; Drug therapy ; Equilibrative Nucleoside Transporter 1 - antagonists & inhibitors ; Equilibrative Nucleoside Transporter 1 - metabolism ; Female ; Heart - drug effects ; Heart - physiopathology ; Heart attacks ; In Vitro Techniques ; Inhibitor drugs ; Myocardial Infarction - etiology ; Myocardial Infarction - metabolism ; Myocardial Infarction - pathology ; Myocardial Infarction - physiopathology ; Myocardial Infarction - prevention & control ; Myocardial Ischemia - complications ; Myocardial Reperfusion Injury - etiology ; Myocardial Reperfusion Injury - metabolism ; Myocardial Reperfusion Injury - pathology ; Myocardial Reperfusion Injury - physiopathology ; Myocardial Reperfusion Injury - prevention & control ; Myocardium - metabolism ; Myocardium - pathology ; Perfusion ; Rats ; Rats, Wistar ; Rodents ; Tetrahydroisoquinolines - pharmacology ; Tetrahydroisoquinolines - therapeutic use ; Thioinosine - analogs & derivatives ; Thioinosine - pharmacology ; Thioinosine - therapeutic use ; Ventricular Function, Left - drug effects ; Ventricular Pressure - drug effects</subject><ispartof>American journal of physiology. Heart and circulatory physiology, 2007-06, Vol.292 (6), p.H2921-H2926</ispartof><rights>Copyright American Physiological Society Jun 2007</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-8239dddecf68b8482909c06ecebccc97ecf7b75a8a139c3c832486fa74a76aea3</citedby><cites>FETCH-LOGICAL-c422t-8239dddecf68b8482909c06ecebccc97ecf7b75a8a139c3c832486fa74a76aea3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3026,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17293492$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhu, Z</creatorcontrib><creatorcontrib>Hofmann, P. A</creatorcontrib><creatorcontrib>Buolamwini, J. K</creatorcontrib><title>Cardioprotective effects of novel tetrahydroisoquinoline analogs of nitrobenzylmercaptopurine riboside in an isolated perfused rat heart model of acute myocardial infarction</title><title>American journal of physiology. Heart and circulatory physiology</title><addtitle>Am J Physiol Heart Circ Physiol</addtitle><description><![CDATA[1 Department of Pharmaceutical Sciences, College of Pharmacy, and 2 Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
Submitted 10 November 2005
; accepted in final form 2 February 2007
We have investigated the cardioprotective effects of novel tetrahydroisoquinoline nitrobenzylmercaptopurine riboside (NBMPR) analog nucleoside transport (NT) inhibitors, compounds 2 and 4, in isolated perfused rat hearts. Langendorff-perfused heart preparations were subjected to 10 min of treatment with compound 2, compound 4, or vehicle (control) followed by 30 min of global ischemia and 120 min of reperfusion. For determination of infarct size, reperfusion time was 180 min. At 1 µM, compounds 2 and 4 provided excellent cardioprotection, with left ventricular developed pressure (LVDP) recovery and end-diastolic pressure (EDP) increase of 82.9 ± 4.0% ( P < 0.001) and 14.1 ± 2.0 mmHg ( P < 0.03) for compound 2-treated hearts and 79.2 ± 5.9% ( P < 0.002) and 7.5 ± 2.7 mmHg ( P < 0.01) for compound 4-treated hearts compared with 41.6 ± 5.2% and 42.5 ± 6.5 mmHg for control hearts. LVDP recovery and EDP increase were 64.1 ± 4.2% and 29.1 ± 2.5 mmHg for hearts treated with 1 µM NBMPR. Compound 4 was the best cardioprotective agent, affording significant cardioprotection, even at 0.1 µM, with LVDP recovery and EDP increase of 76.0 ± 4.9% ( P < 0.003) and 14.1 ± 1.0 mmHg ( P < 0.03). At 1 µM, compound 4 and NBMPR reduced infarct size, with infarct area-to-total risk area ratios of 29.13 ± 3.17 ( P < 0.001) for compound 4 and 37.5 ± 3.42 ( P < 0.01) for NBMPR vs. 51.08 ± 5.06% for control hearts. Infarct size was more effectively reduced by compound 4 than by NBMPR ( P < 0.02). These new tetrahydroisoquinoline NBMPR analogs are not only potent cardioprotective agents but are, also, more effective than NBMPR in this model.
cardioprotection; nucleoside transport inhibitors; left ventricular developed pressure; end-diastolic pressure; ischemia; reperfusion; adenosine potentiation; infarct size reduction
Address for reprint requests and other correspondence: J. K. Buolamwini, Dept. Pharmaceutical Sciences, College of Pharmacy, Univ. of Tennessee Health Science Center, 847 Monroe Ave., Suite 327, Memphis, TN 38163 (e-mail: jbuolamwini{at}utmem.edu )]]></description><subject>Animals</subject><subject>Cardiology</subject><subject>Cardiotonic Agents - pharmacology</subject><subject>Cardiotonic Agents - therapeutic use</subject><subject>Chemical compounds</subject><subject>Clinical outcomes</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug therapy</subject><subject>Equilibrative Nucleoside Transporter 1 - antagonists & inhibitors</subject><subject>Equilibrative Nucleoside Transporter 1 - metabolism</subject><subject>Female</subject><subject>Heart - drug effects</subject><subject>Heart - physiopathology</subject><subject>Heart attacks</subject><subject>In Vitro Techniques</subject><subject>Inhibitor drugs</subject><subject>Myocardial Infarction - etiology</subject><subject>Myocardial Infarction - metabolism</subject><subject>Myocardial Infarction - pathology</subject><subject>Myocardial Infarction - physiopathology</subject><subject>Myocardial Infarction - prevention & control</subject><subject>Myocardial Ischemia - complications</subject><subject>Myocardial Reperfusion Injury - etiology</subject><subject>Myocardial Reperfusion Injury - metabolism</subject><subject>Myocardial Reperfusion Injury - pathology</subject><subject>Myocardial Reperfusion Injury - physiopathology</subject><subject>Myocardial Reperfusion Injury - prevention & control</subject><subject>Myocardium - metabolism</subject><subject>Myocardium - pathology</subject><subject>Perfusion</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Rodents</subject><subject>Tetrahydroisoquinolines - pharmacology</subject><subject>Tetrahydroisoquinolines - therapeutic use</subject><subject>Thioinosine - analogs & derivatives</subject><subject>Thioinosine - pharmacology</subject><subject>Thioinosine - therapeutic use</subject><subject>Ventricular Function, Left - drug effects</subject><subject>Ventricular Pressure - drug effects</subject><issn>0363-6135</issn><issn>1522-1539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kcFu1DAQhi0EotvCEyAhi3u2sZ04sTihFaWVKnEpZ8uxx41XSZzaTiG8E--It7tQLpw80vzf75n5EXpHyi0hNb1U-7kHFdK2JESQLS3L-gXa5A4tSM3ES7QpGWcFJ6w-Q-cx7susaDh7jc5IQwWrBN2gXzsVjPNz8Al0co-AwdpcRewtnvwjDDhBCqpfTfAu-ofFTX5wE2A1qcHfH3UuBd_B9HMdRghazcnPSziIgut8dAawmzKAs8GgEhg8Q7BLzEVQCT9tgUdv8mfZTeklAR5Xrw-jqSGzVoU8nJ_eoFdWDRHent4L9O3q893uurj9-uVm9-m20BWlqWgpE8YY0Ja3XVu1VJRClxw0dFpr0eRG0zW1ahVhQjPdMlq13KqmUg1XoNgF-nD0zXd5WCAmufdLyAtHSanglLaUZxE7inTwMQawcg5uVGGVpJSHhOSfhORTQvKQUKben6yXbgTzzJwiyYLLo6B39_13F0DO_Rqdz8denx2poJLL6_yQTHz8P3G1DMMd_Eh_0X9IORvLfgMoIrw0</recordid><startdate>20070601</startdate><enddate>20070601</enddate><creator>Zhu, Z</creator><creator>Hofmann, P. A</creator><creator>Buolamwini, J. K</creator><general>American Physiological Society</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>7QP</scope><scope>7QR</scope><scope>7TS</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20070601</creationdate><title>Cardioprotective effects of novel tetrahydroisoquinoline analogs of nitrobenzylmercaptopurine riboside in an isolated perfused rat heart model of acute myocardial infarction</title><author>Zhu, Z ; Hofmann, P. A ; Buolamwini, J. K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-8239dddecf68b8482909c06ecebccc97ecf7b75a8a139c3c832486fa74a76aea3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Cardiology</topic><topic>Cardiotonic Agents - pharmacology</topic><topic>Cardiotonic Agents - therapeutic use</topic><topic>Chemical compounds</topic><topic>Clinical outcomes</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug therapy</topic><topic>Equilibrative Nucleoside Transporter 1 - antagonists & inhibitors</topic><topic>Equilibrative Nucleoside Transporter 1 - metabolism</topic><topic>Female</topic><topic>Heart - drug effects</topic><topic>Heart - physiopathology</topic><topic>Heart attacks</topic><topic>In Vitro Techniques</topic><topic>Inhibitor drugs</topic><topic>Myocardial Infarction - etiology</topic><topic>Myocardial Infarction - metabolism</topic><topic>Myocardial Infarction - pathology</topic><topic>Myocardial Infarction - physiopathology</topic><topic>Myocardial Infarction - prevention & control</topic><topic>Myocardial Ischemia - complications</topic><topic>Myocardial Reperfusion Injury - etiology</topic><topic>Myocardial Reperfusion Injury - metabolism</topic><topic>Myocardial Reperfusion Injury - pathology</topic><topic>Myocardial Reperfusion Injury - physiopathology</topic><topic>Myocardial Reperfusion Injury - prevention & control</topic><topic>Myocardium - metabolism</topic><topic>Myocardium - pathology</topic><topic>Perfusion</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Rodents</topic><topic>Tetrahydroisoquinolines - pharmacology</topic><topic>Tetrahydroisoquinolines - therapeutic use</topic><topic>Thioinosine - analogs & derivatives</topic><topic>Thioinosine - pharmacology</topic><topic>Thioinosine - therapeutic use</topic><topic>Ventricular Function, Left - drug effects</topic><topic>Ventricular Pressure - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhu, Z</creatorcontrib><creatorcontrib>Hofmann, P. A</creatorcontrib><creatorcontrib>Buolamwini, J. K</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><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><jtitle>American journal of physiology. Heart and circulatory physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhu, Z</au><au>Hofmann, P. A</au><au>Buolamwini, J. K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cardioprotective effects of novel tetrahydroisoquinoline analogs of nitrobenzylmercaptopurine riboside in an isolated perfused rat heart model of acute myocardial infarction</atitle><jtitle>American journal of physiology. Heart and circulatory physiology</jtitle><addtitle>Am J Physiol Heart Circ Physiol</addtitle><date>2007-06-01</date><risdate>2007</risdate><volume>292</volume><issue>6</issue><spage>H2921</spage><epage>H2926</epage><pages>H2921-H2926</pages><issn>0363-6135</issn><eissn>1522-1539</eissn><coden>AJPPDI</coden><abstract><![CDATA[1 Department of Pharmaceutical Sciences, College of Pharmacy, and 2 Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
Submitted 10 November 2005
; accepted in final form 2 February 2007
We have investigated the cardioprotective effects of novel tetrahydroisoquinoline nitrobenzylmercaptopurine riboside (NBMPR) analog nucleoside transport (NT) inhibitors, compounds 2 and 4, in isolated perfused rat hearts. Langendorff-perfused heart preparations were subjected to 10 min of treatment with compound 2, compound 4, or vehicle (control) followed by 30 min of global ischemia and 120 min of reperfusion. For determination of infarct size, reperfusion time was 180 min. At 1 µM, compounds 2 and 4 provided excellent cardioprotection, with left ventricular developed pressure (LVDP) recovery and end-diastolic pressure (EDP) increase of 82.9 ± 4.0% ( P < 0.001) and 14.1 ± 2.0 mmHg ( P < 0.03) for compound 2-treated hearts and 79.2 ± 5.9% ( P < 0.002) and 7.5 ± 2.7 mmHg ( P < 0.01) for compound 4-treated hearts compared with 41.6 ± 5.2% and 42.5 ± 6.5 mmHg for control hearts. LVDP recovery and EDP increase were 64.1 ± 4.2% and 29.1 ± 2.5 mmHg for hearts treated with 1 µM NBMPR. Compound 4 was the best cardioprotective agent, affording significant cardioprotection, even at 0.1 µM, with LVDP recovery and EDP increase of 76.0 ± 4.9% ( P < 0.003) and 14.1 ± 1.0 mmHg ( P < 0.03). At 1 µM, compound 4 and NBMPR reduced infarct size, with infarct area-to-total risk area ratios of 29.13 ± 3.17 ( P < 0.001) for compound 4 and 37.5 ± 3.42 ( P < 0.01) for NBMPR vs. 51.08 ± 5.06% for control hearts. Infarct size was more effectively reduced by compound 4 than by NBMPR ( P < 0.02). These new tetrahydroisoquinoline NBMPR analogs are not only potent cardioprotective agents but are, also, more effective than NBMPR in this model.
cardioprotection; nucleoside transport inhibitors; left ventricular developed pressure; end-diastolic pressure; ischemia; reperfusion; adenosine potentiation; infarct size reduction
Address for reprint requests and other correspondence: J. K. Buolamwini, Dept. Pharmaceutical Sciences, College of Pharmacy, Univ. of Tennessee Health Science Center, 847 Monroe Ave., Suite 327, Memphis, TN 38163 (e-mail: jbuolamwini{at}utmem.edu )]]></abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>17293492</pmid><doi>10.1152/ajpheart.01191.2005</doi></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0363-6135 |
| ispartof | American journal of physiology. Heart and circulatory physiology, 2007-06, Vol.292 (6), p.H2921-H2926 |
| issn | 0363-6135 1522-1539 |
| language | eng |
| recordid | cdi_crossref_primary_10_1152_ajpheart_01191_2005 |
| source | MEDLINE; American Physiological Society; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Cardiology Cardiotonic Agents - pharmacology Cardiotonic Agents - therapeutic use Chemical compounds Clinical outcomes Dose-Response Relationship, Drug Drug therapy Equilibrative Nucleoside Transporter 1 - antagonists & inhibitors Equilibrative Nucleoside Transporter 1 - metabolism Female Heart - drug effects Heart - physiopathology Heart attacks In Vitro Techniques Inhibitor drugs Myocardial Infarction - etiology Myocardial Infarction - metabolism Myocardial Infarction - pathology Myocardial Infarction - physiopathology Myocardial Infarction - prevention & control Myocardial Ischemia - complications Myocardial Reperfusion Injury - etiology Myocardial Reperfusion Injury - metabolism Myocardial Reperfusion Injury - pathology Myocardial Reperfusion Injury - physiopathology Myocardial Reperfusion Injury - prevention & control Myocardium - metabolism Myocardium - pathology Perfusion Rats Rats, Wistar Rodents Tetrahydroisoquinolines - pharmacology Tetrahydroisoquinolines - therapeutic use Thioinosine - analogs & derivatives Thioinosine - pharmacology Thioinosine - therapeutic use Ventricular Function, Left - drug effects Ventricular Pressure - drug effects |
| title | Cardioprotective effects of novel tetrahydroisoquinoline analogs of nitrobenzylmercaptopurine riboside in an isolated perfused rat heart model of acute myocardial infarction |
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