Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor.
We used pharmacological agents and genetic methods to determine whether the potent A(3) adenosine receptor (AR) agonist 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (Cl-IB-MECA) protects against myocardial ischemia/reperfusion injury in mice via the A(3)AR or via interactions with other AR subtypes. Pretreating wild-type (WT) mice with Cl-IB-MECA reduced myocardial infarct size induced by 30 min of coronary occlusion and 24 h of reperfusion at doses (30 and 100 mug/kg) that concomitantly reduced blood pressure and stimulated systemic histamine release. The A(3)AR-selective antagonist MRS 1523 [3-propyl-6-ethyl-5[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridine-carboxylate], but not the A(2A)AR antagonist ZM 241385 [4-{2-7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol], blocked the reduction in infarct size provided by Cl-IB-MECA, suggesting a mechanism involving the A(3)AR. To further examine the selectivity of Cl-IB-MECA, we assessed its cardioprotective effectiveness in A(3)AR gene "knock-out" (A(3)KO) mice. Cl-IB-MECA did not reduce myocardial infarct size in A(3)KO mice in vivo and did not protect isolated perfused hearts obtained from A(3)KO mice from injury induced by global ischemia and reperfusion. Additional studies using WT mice treated with compound 48/80 [condensation product of p-methoxyphenethyl methylamine with formaldehyde] to deplete mast cell contents excluded the possibility that Cl-IB-MECA was cardioprotective by releasing mediators from mast cells. These data demonstrate that Cl-IB-MECA protects against myocardial ischemia/reperfusion injury in mice principally by activating the A(3)AR.
Ge
Zhi-Dong
ZD
Department of Pharmacology and Toxicology and the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Peart
Jason N
JN
Kreckler
Laura M
LM
Wan
Tina C
TC
Jacobson
Marlene A
MA
Gross
Garrett J
GJ
Auchampach
John A
JA
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000097:blood; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D043684:Receptor, Adenosine A3 / Q000235:genetics; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
C419146:2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate; D058909:Adenosine A3 Receptor Agonists; D002316:Cardiotonic Agents; D011725:Pyridines; D043684:Receptor, Adenosine A3; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D003189:p-Methoxy-N-methylphenethylamine; D006632:Histamine; D000242:Cyclic AMP; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide