n-((1s-trans)-2-hydroxycyclopentyl)adenosine and Coronary-Disease

Ischemic preconditioning is known to protect the human heart from ischemic injury during coronary artery bypass graft (CABG) surgery but is not practised routinely. Adenosine A1 receptor agonists may confer protection in this setting by mimicking preconditioning. The aim of this study was to compare preconditioning, by ischemia or an adenosine A1 receptor agonist (GR79236X), with an established method of myocardial protection in CABG, namely intermittent cross-clamp fibrillation.. In this prospective double-blind study, 30 CABG patients were randomised to receive: (a) intermittent cross-clamp fibrillation (control), (b) pharmacological preconditioning (GR79236X), or (c) ischemic preconditioning (two 3-min periods of ischemia, each followed by 2 min of reperfusion). Surgery was performed under standardised conditions by one surgeon (WBP). The primary endpoint was cardiac troponin T release.. Mean cardiopulmonary bypass time was 91+/-11.6 (S.D.) min. Mean ischemic time was 33+/-5.5 (S.D.) min with no inter-group difference. Mean troponin T at 72 h was highest in the control group (1.32+/-0.99 (S.D.) microg/l), similar in the GR79236X group (1.22+/-1.22 (S.D.) microg/l; P=0.85) and significantly reduced in the ischemic preconditioning group (0.58+/-0.40 (S.D.) microg/l; P=0.04).. Ischemic preconditioning is superior to the other techniques at limiting myocardial necrosis during CABG. Pharmacological preconditioning may confer some benefit but this was not statistically shown using a specific adenosine A1 agonist (GR79236X).

Topics: Adenosine; Adult; Aged; Coronary Artery Bypass; Coronary Disease; Double-Blind Method; Female; Humans; Ischemic Preconditioning, Myocardial; Male; Middle Aged; Myocardial Ischemia; Myocardium; Necrosis; Prospective Studies; Purinergic P1 Receptor Agonists; Troponin T

The cardioprotective effects of the selective adenosine A1-receptor agonist, GR79236 (N-[(1S, trans)-2-hydroxycyclopentyl]adenosine), were examined in a porcine model of myocardial ischaemia-reperfusion injury. When pigs were subjected to a 50-min coronary artery occlusion followed by 3-h reperfusion, GR79236 (10 nmol/kg, i.v.) significantly reduced infarct size whether given 10 min before the onset of ischaemia or reperfusion. This effect was independent of the bradycardia induced by GR79236, as it was also observed in animals in which heart rate was maintained by electrical pacing. However, GR79236 administered 10 min after reperfusion did not reduce infarct size. GR79236 had no effect on the incidence or outcome of ventricular dysrhythmias in this pig model of infarction. Similarly, ischaemic preconditioning (IPC, 2 x 10-min ischaemia and 10-min reperfusion) significantly reduced infarct size. The selective adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 3.3 micromol/kg, i.v.), abolished the haemodynamic and cardioprotective effects of GR79236 and the cardioprotective effects of IPC in anaesthetised pigs. In conclusion, GR79236 exerted a marked cardioprotective effect in a porcine model of myocardial ischaemia-reperfusion injury, provided that it was administered before reperfusion. This suggests that GR79236 may have clinical utility in the treatment of various aspects of ischaemic heart disease.

Topics: Adenosine; Anesthesia; Animals; Blood Pressure; Coronary Disease; Female; Heart Rate; Male; Molecular Structure; Myocardial Infarction; Purinergic P1 Receptor Agonists; Reperfusion Injury; Swine; Time Factors; Ventricular Dysfunction; Xanthines