title: Aldose reductase inhibition alone or combined with an adenosine A(3) agonist reduces ischemic myocardial injury.
abstract: 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.affiliation: Department of Cardiovascular and Metabolic Diseases, Pfizer, Incorporated, Groton, Connecticut 06340, USA. w_ross_tracey@groton.pfizer.com
authors.forename: W R
authors.initials: WR
authors.lastname: Tracey
authors.forename: W P
authors.initials: WP
authors.lastname: Magee
authors.forename: C A
authors.initials: CA
authors.lastname: Ellery
authors.forename: J T
authors.initials: JT
authors.lastname: MacAndrew
authors.forename: A H
authors.initials: AH
authors.lastname: Smith
authors.forename: D R
authors.initials: DR
authors.lastname: Knight
authors.forename: P J
authors.initials: PJ
authors.lastname: Oates
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D052160:Benzothiazoles; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010793:Phthalazines / Q000494:pharmacology*; D058906:Purinergic P1 Receptor Agonists; D011817:Rabbits; D043684:Receptor, Adenosine A3; D013012:Sorbitol / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D052160:Benzothiazoles; C116825:CB MECA; D004791:Enzyme Inhibitors; D010793:Phthalazines; D058906:Purinergic P1 Receptor Agonists; D043684:Receptor, Adenosine A3; D013844:Thiazoles; C067172:zopolrestat; D013012:Sorbitol; D000449:Aldehyde Reductase; D000241:Adenosine