n(6)-cyclopentyladenosine and Myocardial-Infarction

Mild hypothermia (32°C-34°C) exerts a potent cardioprotection in animal models of myocardial infarction. Recently, it has been proposed that this beneficial effect is related to survival signaling. We, therefore, hypothesized that the well-known cardioprotective pathways dependent on adenosine and/or opioid receptors could be the trigger of hypothermia-induced salvage. Open-chest rabbits were accordingly exposed to 30 minutes of coronary artery occlusion (CAO) under normothermic (NT) or hypothermic ([HT] 32°C) conditions. In the latter, hypothermia was induced by total liquid ventilation with temperature-controlled perfluorocarbons in order to effect ultrafast cooling and to accurately control cardiac temperature. After 4 hours of reperfusion, infarct and no-reflow zone sizes were assessed and quantified as a percentage of the risk zone. In animals experiencing HT ischemia, the infarct size was dramatically reduced as compared to NT animals (9% ± 3% vs 55% ± 2% of the risk zone, respectively). Importantly, administration of opioid and adenosine receptor antagonists (naloxone [6 mg/kg iv] and 8-(p-sulfophenyl) theophylline [20 mg/kg iv], respectively) did not alter the infarct size or affect the cardioprotective effect of hypothermia. Doses of these 2 antagonists were appropriately chosen since they blunted infarct size reduction induced by selective opioid or adenosine receptor stimulation with morphine (0.3 mg/kg iv) or N (6)-cyclopentyladenosine ([CPA] 100 μg/kg iv), respectively. Therefore, the cardioprotective effect of mild hypothermia is not triggered by either opioid or adenosine receptor activation, suggesting the involvement of other cardioprotective pathways.

Topics: Adenosine; Analgesics, Opioid; Animals; Fluorocarbons; Hypothermia, Induced; Morphine; Myocardial Infarction; Naloxone; Narcotic Antagonists; Purinergic P1 Receptor Antagonists; Rabbits; Receptors, Opioid; Receptors, Purinergic P1; Theophylline; Time Factors

Ring-constrained adenosine analogues have been designed to act as dual agonists at tissue-protective A(1) and A(3) adenosine receptors (ARs). 9-Ribosides transformed into the ring-constrained (N)-methanocarba-2-chloro-5'-uronamides consistently lost affinity at A(1)/A(2A)ARs and gained at A(3)AR. Among 9-riboside derivatives, only N(6)-cyclopentyl and 7-norbornyl moieties were extrapolated for mixed A(1)/A(3) selectivity and rat/human A(3)AR equipotency. Consequently, 2 was balanced in affinity and potency at A(1)/A(3)ARs as envisioned and dramatically protected in an intact heart model of global ischemia and reperfusion.

Topics: Adenosine; Adenosine A1 Receptor Agonists; Adenosine A2 Receptor Agonists; Adenosine A3 Receptor Agonists; Animals; Cardiotonic Agents; CHO Cells; Cricetinae; Drug Design; Humans; Mice; Myocardial Infarction; Receptor, Adenosine A1; Receptor, Adenosine A2A; Receptor, Adenosine A3; Reperfusion Injury; Ventricular Function, Left

We investigated the influence of coronary artery reperfusion (CAR) duration on the infarct-limiting properties of adenosine A(1)-receptor stimulation-induced delayed preconditioning (A(1)-DPC) compared with ischemia-induced delayed preconditioning (I-DPC). Sixty-one chronically instrumented conscious rabbits successfully underwent the following protocol. On day 1, rabbits were randomly divided into four groups: control (saline, iv), I-DPC (six 4-min coronary artery occlusion/4-min reperfusion cycles), A(1)-DPC(100) (N(6)-cyclopentyladenosine, 100 microg/kg iv), and A(1)-DPC(400) (N(6)-cyclopentyladenosine, 400 microg/kg iv). On day 2 (i.e., 24 h later), rabbits underwent a 30-min coronary artery occlusion after which CAR was started and maintained for either 3 or 72 h. Infarct size (percentage of the area at risk) was determined by triphenyltetrazolium chloride staining. After 3 h of CAR, I-DPC, A(1)-DPC(100), and A(1)-DPC(400) significantly decreased infarct size (36 +/- 5, 41 +/- 4, 38 +/- 5%, respectively) compared with control (55 +/- 3%). After 72 h of CAR, infarct sizes were not significantly different among the four groups. This result was confirmed by histologic analysis. Thus A(1)-DPC at the two investigated doses, as well as I-DPC, decreased infarct size after 3 h but not 72 h of CAR.

Topics: Adenosine; Animals; Cardiac Catheterization; Coronary Vessels; Disease Models, Animal; Disease Progression; Heart Ventricles; Hemodynamics; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Purinergic P1 Receptor Agonists; Rabbits; Receptors, Purinergic P1; Time Factors; Treatment Outcome; Wakefulness

1. The goal of this study was to investigate the effects of the delayed pharmacological preconditioning produced by an adenosine A(1)-receptor agonist (A(1)-DPC) against ventricular arrhythmias induced by ischaemia and reperfusion, compared to those of ischaemia-induced delayed preconditioning (I-DPC). 2. Eighty-nine instrumented conscious rabbits underwent a 2 consecutive days protocol. On day 1, rabbits were randomly divided into four groups: 'Control' (saline, i.v.), 'I-DPC' (six 4-min coronary artery occlusion/4-min reperfusion cycles), 'A(1)-DPC(100)' (N(6)-cyclopentyladenosine, 100 microg kg(-1), i.v.), and 'A(1)-DPC(400)' (N(6)-cyclopentyladenosine, 400 microg kg(-1), i.v.). On day 2, i.e., 24 h later, the incidence and severity of ventricular arrhythmias during a 30-min coronary artery occlusion and subsequent reperfusion were analysed in all animals, using an arrhythmia score. 3. I-DPC, A(1)-DPC(100) and A(1)-DPC(400) significantly reduced the infarct size (34+/-5, 42+/-3 and 43+/-7% of the area at risk, respectively) as compared to Control (55+/-3% of the area at risk). 4. During both ischaemia and reperfusion, neither the incidence nor the severity of ventricular arrhythmias were altered by A(1)-DPC(100), A(1)-DPC(400) or I-DPC as compared to Control. 5. Thus, despite reduction of infarct size induced by delayed preconditioning, A(1)-DPC as well as I-DPC failed to exert any anti-arrhythmic effect in the conscious rabbit model of ischaemia-reperfusion.

Topics: Adenosine; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Disease; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Heart Ventricles; Hemodynamics; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Purinergic P1 Receptor Agonists; Rabbits