n-((1s-trans)-2-hydroxycyclopentyl)adenosine and Myocardial-Ischemia

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 "warm up" effect in angina may represent ischaemic preconditioning, which is mediated by adenosine A(1) receptors in most models.. To investigate the effect of a selective A(1) agonist, GR79236 (GlaxoSmithKline), on exercise induced angina and ischaemic left ventricular dysfunction in patients with coronary artery disease.. A double blind crossover study.. 25 patients with multivessel coronary artery disease.. On mornings one week apart, patients received intravenous GR79236 10 microgram/kg or placebo, and then carried out two supine bicycle exercise tests separated by 30 minutes. Equilibrium radionuclide angiography was done before and during exercise.. The onset of chest pain or 1 mm ST depression was delayed and occurred at a higher rate-pressure product during the second exercise test following either placebo or GR79236. Compared with placebo, GR79236 did not affect these indices during equivalent tests. GR79236 reduced resting global ejection fraction from (mean (SD)) 63 (7)% to 61 (5)% (p < 0.05) by a selective reduction in the regional ejection fraction of "ischaemic" left ventricular sectors (those where the ejection fraction fell during the first exercise test following placebo). Ischaemic sectors showed increased function during the second test following placebo (72 (21)% v 66 (20)%; p = 0.0001), or during the first test following GR79236 (69 (21)% v 66 (20)%; p = 0.0001). Sequential exercise further increased the function of ischaemic sectors even after drug administration.. GR79236 failed to mimic the warm up effect, and warm up occurred even in the presence of this agent. This suggests that ischaemic preconditioning is not an important component of this type of protection. The complex actions of the drug on regional left ventricular function at rest and during exercise suggest several competing A(1) mediated actions.

Topics: Adenosine; Angina Pectoris; Coronary Artery Disease; Cross-Over Studies; Double-Blind Method; Electrocardiography; Exercise; Exercise Test; Female; Hemodynamics; Humans; Hypolipidemic Agents; Injections, Intravenous; Ischemic Preconditioning, Myocardial; Male; Middle Aged; Myocardial Ischemia; Ventricular Dysfunction, Left

1 The cardioprotective effect of N-[(1S, trans)-2-hydroxycyclopentyl]adenosine (GR79236), an adenosine A1 receptor agonist, was compared with that produced by ischaemic preconditioning in an anaesthetized rabbit model of myocardial ischaemia and reperfusion. In addition, we examined the effect of different body core temperatures on GR79236- or ischaemic preconditioning-induced cardioprotection when administered prior to ischaemia, and on cardioprotection induced by GR79236 administered 10 min prior to the onset of reperfusion. 2 When rabbits were subjected to 30 min occlusion of the left coronary artery, followed by 2 h reperfusion, GR79236 (3 x 10(-8) mol kg-1 i.v. (10.5 microg kg-1 i.v.)) or ischaemic preconditioning (5 min ischaemia followed by 5 min reperfusion), administered or applied 10 min prior to the occlusion, significantly limited the development of infarction. The cardioprotective effect of ischaemic preconditioning was significantly greater than that seen after administration of GR79236. Pre-treatment with the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 3.3 x 10(-6) mol kg-1 (1 mg kg-1 i.v.)), prevented the cardioprotective effect of GR79236, but not that of ischaemic preconditioning. 3 Maintaining body core temperature at 38.5 degrees C rather than at 37.0 degrees C did not influence infarct size in control groups of rabbits, but reduced the cardioprotective effect of GR79236 when administered 10 min prior to occlusion or 10 min prior to the onset of reperfusion. The cardioprotective effect of ischaemic preconditioning was not temperature-dependent. 4 In conclusion, myocardial protection conferred by GR79236 in anaesthetized rabbits is mediated via adenosine A1 receptors. Myocardial protection can be conferred when GR79236 is administered before the onset of ischaemia or reperfusion, and is reduced when body core temperature is maintained at 38.5 degrees C rather than at 37.0 degrees C. In contrast, myocardial protection conferred by ischaemic preconditioning is not reduced by adenosine A1 receptor blockade, or by maintaining body core temperature at 38.5 degrees C rather than at 37.0 degrees C. These findings point to distinct differences in the mechanisms of induction of myocardial protection by adenosine A1 receptor agonist and ischaemic preconditioning. They also highlight the need for careful control of body core temperature when investigating the phenomenon of cardioprotection.

Topics: Adenosine; Anesthesia; Animals; Blood Pressure; Body Temperature; Heart Rate; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Purinergic P1 Receptor Agonists; Rabbits; Xanthines