Delayed 24 hours Nomega-nitro-L-arginine methyl ester injection induces pharmacological cardioprotection against reperfusion injury.
Previous studies indicate that adenosine supplementation or nitric oxide synthase (NOS) inhibition during reperfusion exert protective effects against myocardial ischemia-reperfusion (I/R) injury. We wanted to test the hypothesis that NOS inhibition before I/R also protects the myocardium against further injury and aimed to determine the involvement of adenosine receptors in a perfused rat heart model. Rats were injected with 10 mg/kg of L-NAME (N(omega)-nitro-L-arginine methyl ester) or L-NAME + SPT (8-(p-sulfophenyl)-theophylline)--an adenosine antagonist - at 2 x 25 mg/kg or with a saline buffer, 24 hrs prior to heart excision. The hearts, perfused retrogradely were subjected to 60 min of global ischemia followed by 120 min reperfusion. L-NAME decreased NOx (nitrite and nitrate) production (16.2 +/- 3.2 vs. 7.0 +/- 1.8 micromol/L; P<0.05) in vivo and increased the release of troponin I (0.04 +/- 0.01 vs. 0.02 +/- 0.01 microg/L; P<0.05) in the plasma, compared to controls. After 120 min of reperfusion, there was a higher release of adenosine (26.1 +/- 2.2 vs. 2.4 +/- 1.2 nmol/min; P<0.01) and a decrease in troponin I levels (0.19 +/-0.07 vs. 0.59 +/- 0.16 ng/min; P<0.05) in the L-NAME group compared to controls. These results were accompanied by a higher proportion of recovery of left ventricular developed pressure (72.0 +/- 4.0 vs. 60.0 +/- 4.0%; P<0.05) and coronary flow (72.0 +/- 5.0 vs. 51.0 +/- 4.0%; P<0.05) in the L-NAME group. These beneficial effects were not blocked by the adenosine receptor antagonist. The present study reveals that L-NAME protects against I/R injury when the inhibitor is administered 24 hrs before ischemia. The beneficial effects observed in this model appear to be independent of adenosine receptor stimulation.
Davani
S
S
Laboratoire de Pharmacologie et Toxicologie, EA 479, IFR 133, Faculté de Médecine, Besançon, France. siamak.davani@ufc-chu.univ-fcomte.fr
Vergely
C
C
Royer
B
B
Bouhaddi
M
M
Reyssie
H
H
Rochette
L
L
Kantelip
J P
JP
D000241:Adenosine / Q000097:blood / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000209:etiology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology; D013997:Time Factors; D019210:Troponin I / Q000097:blood / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D019210:Troponin I; C026512:arginine methyl ester; D001120:Arginine; D013806:Theophylline; D019001:Nitric Oxide Synthase; D000241:Adenosine