Aldose reductase inhibition alone or combined with an adenosine A(3) agonist reduces ischemic myocardial injury.
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.
Tracey
W R
WR
Department of Cardiovascular and Metabolic Diseases, Pfizer, Incorporated, Groton, Connecticut 06340, USA. w_ross_tracey@groton.pfizer.com
Magee
W P
WP
Ellery
C A
CA
MacAndrew
J T
JT
Smith
A H
AH
Knight
D R
DR
Oates
P J
PJ
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*
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