Vesnarinone limits infarct size via adenosine-dependent mechanisms in the canine heart.
BACKGROUND
Recently, vesnarinone, a synthetic inotropic agent, was reported to inhibit adenosine transport into cells, which may increase adenosine levels in the heart and in turn mediate cardioprotection. Thus, vesnarinone may also have protective effects in sustained ischemia-reperfusion, because adenosine limits infarct size.


RESULTS
In open-chest dogs, the left anterior descending coronary arteries were occluded for 90 minutes followed by 6 hours of reperfusion. Vesnarinone limited infarct size compared with controls (6.8+/-2.2% versus 44.7+/-3.9%), which was completely reversed by a nonselective adenosine receptor antagonist, 8-sulfophenyltheophylline (44.1+/-6.8%), and partially blunted by an inhibitor of ecto-5'-nucleotidase, alpha,beta-methyleneadenosine 5'-diphosphate (AMP-CP, 28.9+/-4.7%). Dipyridamole, an inhibitor of adenosine uptake into cells, only modestly limited infarct size (27.4+/-5.5%). Furthermore, vesnarinone increased adenosine release during coronary hypoperfusion, which was attenuated by AMP-CP. In vitro, vesnarinone increased the activity of ecto-5'-nucleotidase of the myocardium.


CONCLUSIONS
We conclude that vesnarinone potently limits infarct size via adenosine-dependent mechanisms, mainly through activation of ecto-5'-nucleotidase.
Kitakaze
M
M
First Department of Medicine, Osaka University School of Medicine, Suita, Japan.
Minamino
T
T
Funaya
H
H
Node
K
K
Shinozaki
Y
Y
Mori
H
H
Hori
M
M
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000241:Adenosine / Q000378:metabolism / Q000502:physiology*; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004176:Dipyridamole / Q000494:pharmacology; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D015640:Ion Channel Gating / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D015221:Potassium Channels / Q000187:drug effects; D011719:Pyrazines; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000502:physiology; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D015221:Potassium Channels; D011719:Pyrazines; D011804:Quinolines; D018047:Receptors, Purinergic P1; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; C041667:vesnarinone; D000244:Adenosine Diphosphate; D004176:Dipyridamole; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D015720:5'-Nucleotidase; D000241:Adenosine