thioinosine and Myocardial-Infarction

To determine the role of the p-nitrobenzylthioinosine-sensitive equilibrative nucleoside transporter 1 (es-ENT1) in postmyocardial infarction reperfusion injury-mediated ventricular fibrillation and regional dysfunction. We used erythro-9 (2-hydroxy-3-nonyl)-adenine and p-nitrobenzylthioinosine to inhibit both adenosine deamination and transport in a canine model of off pump acute myocardial infarction.. Anesthetized adult dogs (n = 37), instrumented to monitor the percentage of systolic segmental shortening and wall thickening using sonomicrometry, underwent 90 minutes of left anterior descending coronary artery occlusion and 120 minutes of reperfusion. Myocardial coronary blood flow, adenosine triphosphate pool, infarct size, and the incident of ventricular fibrillation and cardioversion were also measured. The dogs received an intravenous infusion of the vehicle (control) or 100 μM of erythro-9 (2-hydroxy-3-nonyl)-adenine and 25 μM p-nitrobenzylthioinosine before ischemia (preconditioning group) or just before reperfusion (postconditioning group).. In the control group, adenosine triphosphate depletion was associated with the accumulation of more inosine than adenosine during ischemia and washed out during reperfusion. Myocardial adenosine and inosine were the major nucleosides in the pre- and postconditioning groups during ischemia and remained detectable during reperfusion. In both groups, recovery of systolic segmental shortening and wall thickening and a reduction in the incidence of ventricular fibrillation (P < .05 vs the control group) coincided with retention of myocardial nucleosides. The infarct size in the 3 groups was not significantly different, independent of myocardial blood flow during ischemia.. Preconditioning or postconditioning with erythro-9 (2-hydroxy-3-nonyl)-adenine/p-nitrobenzylthioinosine significantly reduced the incidence of ventricular fibrillation and cardioversion and attenuated regional contractile dysfunction mediated by postmyocardial infarction reperfusion injury. It is concluded that p-nitrobenzylthioinosine-sensitive equilibrative nucleoside transporter 1 played a major role in these events.

Topics: Adenosine Deaminase Inhibitors; Adenosine Triphosphate; Analysis of Variance; Animals; Coronary Circulation; Dogs; Equilibrative Nucleoside Transporter 1; Ischemic Preconditioning; Least-Squares Analysis; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardial Stunning; Thioinosine; Ventricular Fibrillation

Metformin improves cardiovascular outcomes in patients with type 2 diabetes compared with other glucose-lowering drugs. Experimental studies have shown that metformin can increase the intracellular concentration of adenosine monophosphate, which is a major determinant of the intracellular formation of adenosine. We hypothesize that metformin, given at reperfusion, can limit myocardial infarct size due to increased adenosine receptor stimulation. Isolated perfused hearts from Sprague-Dawley rats were subjected to 35 minutes of regional ischemia and 120 minutes of reperfusion. Perfusion with metformin (50 microM) for the first 15 minutes of reperfusion reduced infarct size (percent area at risk) from 42% +/- 2% to 19% +/- 4% (n >or= 6; P < 0.01), which was blocked by a concomitant perfusion with the adenosine receptor antagonist 8-p-sulfophenyltheophylline (100 microM; 43% +/- 3%) or nitrobenzylthioinosine (a blocker of transmembranous adenosine transport; 1 microM; 45% +/- 5%). In addition, intravenous administration of metformin (5 mg/kg) reduced infarct size in a rat in situ model of myocardial infarction (34% +/- 6% vs. 62% +/- 5%; P < 0.01), which was completely abolished by 8-p-sulfophenyltheophylline (61% +/- 3%). We conclude that metformin, given at reperfusion, reduces infarct size in a rat model of myocardial infarction, which is critically dependent on adenosine receptor stimulation, probably via increased intracellular formation of adenosine.

Topics: Adenosine; Animals; Biological Transport; Hypoglycemic Agents; In Vitro Techniques; Male; Metformin; Myocardial Infarction; Myocardial Reperfusion Injury; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Theophylline; Thioinosine

We have investigated the cardioprotective effects of novel tetrahydroisoquinoline nitrobenzylmercaptopurine riboside (NBMPR) analog nucleoside transport (NT) inhibitors, compounds 2 and 4, in isolated perfused rat hearts. Langendorff-perfused heart preparations were subjected to 10 min of treatment with compound 2, compound 4, or vehicle (control) followed by 30 min of global ischemia and 120 min of reperfusion. For determination of infarct size, reperfusion time was 180 min. At 1 microM, compounds 2 and 4 provided excellent cardioprotection, with left ventricular developed pressure (LVDP) recovery and end-diastolic pressure (EDP) increase of 82.9 +/- 4.0% (P<0.001) and 14.1 +/- 2.0 mmHg (P<0.03) for compound 2-treated hearts and 79.2 +/- 5.9% (P<0.002) and 7.5 +/- 2.7 mmHg (P<0.01) for compound 4-treated hearts compared with 41.6 +/- 5.2% and 42.5 +/- 6.5 mmHg for control hearts. LVDP recovery and EDP increase were 64.1 +/- 4.2% and 29.1 +/- 2.5 mmHg for hearts treated with 1 microM NBMPR. Compound 4 was the best cardioprotective agent, affording significant cardioprotection, even at 0.1 microM, with LVDP recovery and EDP increase of 76.0 +/- 4.9% (P<0.003) and 14.1 +/- 1.0 mmHg (P<0.03). At 1 microM, compound 4 and NBMPR reduced infarct size, with infarct area-to-total risk area ratios of 29.13 +/- 3.17 (P<0.001) for compound 4 and 37.5 +/- 3.42 (P<0.01) for NBMPR vs. 51.08 +/- 5.06% for control hearts. Infarct size was more effectively reduced by compound 4 than by NBMPR (P<0.02). These new tetrahydroisoquinoline NBMPR analogs are not only potent cardioprotective agents but are, also, more effective than NBMPR in this model.

Topics: Animals; Cardiotonic Agents; Dose-Response Relationship, Drug; Equilibrative Nucleoside Transporter 1; Female; Heart; In Vitro Techniques; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Perfusion; Rats; Rats, Wistar; Tetrahydroisoquinolines; Thioinosine; Ventricular Function, Left; Ventricular Pressure

The potential cytoprotective effect of the purine transport inhibitor S-(p-nitrobenzyl)-6-thioinosine (NBTI) in a model of myocardial ischaemia and reperfusion was investigated in the anaesthetised ferret. The left anterior descending coronary artery (LAD) was occluded for 90 min, producing ischaemia in 53 +/- 3% of the left ventricular free wall, followed by 240 min reperfusion. NBTI (0.5 mg kg-1, i.v.) was given prior to ischaemia or prior to reperfusion. In addition the effect of purine transport inhibition was investigated in animals subjected to ischaemia without reperfusion. NBTI reduced infarct size from 84.0 +/- 1.7 to 71.4 +/- 3.7% of the area at risk (P < 0.05) when given prior to occlusion of the LAD. NBTI was ineffective however when given 15 min prior to reperfusion. NBTI had no effect upon infarct size produced by ischaemia without reperfusion. The effect of NBTI was independent of significant changes in myocardial blood flow during ischaemia and reperfusion or upon neutrophil infiltration.

Topics: Adenosine; Animals; Atenolol; Blood Gas Analysis; Blood Pressure; Coronary Circulation; Ferrets; Heart Rate; Hemodynamics; Injections, Intravenous; Leukocyte Count; Male; Microspheres; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Peroxidase; Thioinosine