Document Detail


Aldose reductase inhibition alone or combined with an adenosine A(3) agonist reduces ischemic myocardial injury.
MedLine Citation:
PMID:  11009428     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
This study investigated whether aldose reductase (AR) inhibition with zopolrestat, either alone or in combination with an adenosine A(3)-receptor agonist (CB-MECA), reduced myocardial ischemic injury in rabbit hearts subjected to 30 min of regional ischemia and 120 min of reperfusion. Zopolrestat reduced infarct size by up to 61%, both in vitro (2 nM to 1 microM; EC(50) = 24 nM) and in vivo (50 mg/kg). Zopolrestat reduced myocardial sorbitol concentration (index of AR activity) by >50% (control, 15.0 +/- 2.2 nmol/g; 200 nM zopolrestat, 6.7 +/- 1.3 nmol/g). A modestly cardioprotective concentration of CB-MECA (0.2 nM) allowed a 50-fold reduction in zopolrestat concentration while providing a similar reduction in infarct size (infarct area/area at risk: control, 62 +/- 2%; 1 microM zopolrestat, 24 +/- 5%; 20 nM zopolrestat plus 0.2 nM CB-MECA, 20 +/- 4%). In conclusion, AR inhibition is cardioprotective both in vitro and in vivo. Furthermore, combining zopolrestat with an A(3) agonist allows a reduction in the zopolrestat concentration while maintaining an equivalent degree of cardioprotection.
Authors:
W R Tracey; W P Magee; C A Ellery; J T MacAndrew; A H Smith; D R Knight; P J Oates
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  279     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2000 Oct 
Date Detail:
Created Date:  2000-10-23     Completed Date:  2000-11-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  H1447-52     Citation Subset:  IM    
Affiliation:
Department of Cardiovascular and Metabolic Diseases, Pfizer, Incorporated, Groton, Connecticut 06340, USA. w_ross_tracey@groton.pfizer.com
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MeSH Terms
Descriptor/Qualifier:
Adenosine / analogs & derivatives*,  pharmacology*
Aldehyde Reductase / antagonists & inhibitors*
Animals
Benzothiazoles
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology*
Male
Myocardial Ischemia / pathology*
Myocardium / metabolism,  pathology
Phthalazines / pharmacology*
Rabbits
Receptor, Adenosine A3
Receptors, Purinergic P1 / agonists*
Sorbitol / metabolism
Thiazoles / pharmacology*
Chemical
Reg. No./Substance:
0/Benzothiazoles; 0/CB MECA; 0/Enzyme Inhibitors; 0/Phthalazines; 0/Receptor, Adenosine A3; 0/Receptors, Purinergic P1; 0/Thiazoles; 110703-94-1/zopolrestat; 50-70-4/Sorbitol; 58-61-7/Adenosine; EC 1.1.1.21/Aldehyde Reductase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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