pentostatin and Myocardial-Infarction

In order to examine the relationship between local adenosine concentrations before, during, and after ischemia and the extent of ischemic myocardial damage, measurements of interstitial fluid (ISF) nucleosides were made using microdialysis probes implanted in the ischemic region of isoflurane anesthetized Micropigs undergoing 60' coronary artery occlusion (CAO) and 3 h of reperfusion (REP). Nucleoside concentrations in the dialysate collected from the microdialysis probes were used as an index of ISF levels. Dialysate nucleoside concentrations (ADO, inosine and hypoxanthine), myocardial infarct size, and myocardial blood flow (MBF) were determined in control animals (n = 6), animals preconditioned with a single 10' cycle of CAO and REP (PC, n = 6), and those treated with the adenosine deaminase inhibitor pentostatin (n = 6, 0.2 mg/Kg i.v. 30' prior to CAO). The brief PC occlusion resulted in a transient but significant increase in dialysate ADO (6.7 +/- 1.8 microM vs. 0.67 +/- 0.1 microM at baseline). Pentostatin administration had no significant effect on either dialysate nucleosides or MBF at baseline. During the 60' CAO, dialysate ADO increased in control animals. In PC animals, however, dialysate ADO during CAO was lower than control. Pretreatment with pentostatin resulted in a six-fold augmentation in dialysate ADO during the 60 min CAO when compared to the control values (110.62 +/- 30.2 microM vs. 16.31 +/- 2.1 microM at 60 min of ischemia). Pentostatin also resulted in a significant reduction in the accumulation of inosine and hypoxanthine, indicating inhibition of adenosine deaminase activity. There were no significant differences in MBF between groups at any time point. Following 3 h REP, infarct size was 35.4 +/- 5.5%, 8.1 +/- 1.5% and 8.3 +/- 1.8% of the region at risk in control, PC, and pentostatin groups, respectively. These data suggest that marked increase in ISF ADO during CAO, may be as effective in reducing INF as a modest increase in ISF ADO prior to prolonged CAO.

Topics: Adenosine; Adenosine Deaminase Inhibitors; Animals; Blood Flow Velocity; Disease Models, Animal; Enzyme Inhibitors; Extracellular Space; Female; Ischemic Preconditioning, Myocardial; Male; Microdialysis; Myocardial Infarction; Myocardial Ischemia; Pentostatin; Swine; Swine, Miniature

The objectives were to determine the effects of the adenosine deaminase inhibitor pentostatin (deoxycoformycin) on interstitial fluid (ISF) adenosine before, during, and after myocardial ischaemia and to ascertain whether augmented endogenous ISF adenosine reduces myocardial infarction.. Untreated anaesthetised dogs (n = 11) were compared to dogs treated with intravenous pentostatin 30 min before ischaemia (0.2 mg.kg-1; n = 11). The changes in ISF adenosine, adenosine metabolites, and lactate were assessed by cardiac microdialysis, using dialysate concentrations as indices of ISF levels. Both groups were exposed to 60 min of regional myocardial ischaemia followed by 3 h of reperfusion.. Although ISF adenosine increased during ischaemia in untreated animals, inosine and hypoxanthine were the predominant purine metabolites which accumulated in the ISF. Pentostatin increased dialysate adenosine 3.5-fold before ischaemia, resulted in a sustained and pronounced augmentation of adenosine during ischaemia, and maintained the raised ISF adenosine during early reperfusion. However, the augmentation of ISF adenosine was not associated with a reduction in infarct size [untreated = 33.3(SEM 4.8)% of the area at risk; pentostatin treated = 35.6(4.6)% of the area at risk], nor did pentostatin alter the ischaemia induced increase in ISF lactate. Plasma adenosine, as measured by a microdialysis probe in the femoral artery, increased in pentostatin treated animals upon reperfusion, leading to systemic hypotension, increased blood flow in the non-ischaemic region, and an attenuated reactive hyperaemia in the ischaemic region.. Although inhibition of adenosine deaminase effectively enhances ISF adenosine before and during ischaemia, the increase before ischaemia does not "precondition" the myocardium, nor does the augmentation of adenosine during and after ischaemia attenuate necrosis in this model of ischaemia. Therefore, the enhancement of ISF adenosine to the extent provided by adenosine deaminase inhibition alone is not sufficient to protect the heart in the way seen with ischaemic preconditioning.

Topics: Adenosine; Adenosine Deaminase Inhibitors; Animals; Coronary Circulation; Dogs; Extracellular Space; Female; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Pentostatin; Regional Blood Flow

Adenosine receptor activation has been assumed to play a role in the cardioprotective effect of ischemic preconditioning. The actions of adenosine are terminated by the naturally occurring substance adenosine deaminase. We determined whether 2'-deoxycoformycin (DCF), a potent inhibitor of adenosine deaminase, could mimic the effect of preconditioning in nonpreconditioned rats and potentiate the salutary effect of preconditioning in preconditioned rats. We assessed the effect of DCF on myocardial infarct size and the incidence of ventricular arrhythmias in four groups of anesthetized rats: control (nonpreconditioned) + vehicle, control + DCF, preconditioned + vehicle, and preconditioned + DCF. All rats underwent 90 minutes of coronary artery occlusion followed by 4 hours of reperfusion, while preconditioned rats received three cycles of 3-minute episodes of ischemia and 5 minutes of reperfusion before the 90-minute occlusion. Following 4 hours of reperfusion, area at risk was determined by intravenous injection of blue dye during a brief coronary occlusion, and area of necrosis was determined by incubation of heart slices in triphenyltetrazolium chloride. In the nonpreconditioned control rats receiving vehicle, myocardial infarct size expressed as a percentage of the area at risk averaged 44.8 +/- 7.6%. Pretreatment with DCF had no effect on infarct size (49.4 +/- 4.9%) in the nonpreconditioned control rats. Both the preconditioned+vehicle (19.2 +/- 7.8%) and the preconditioned + DCF (17.9 +/- 5.1%) groups had a significant reduction in infarct size (p < 0.05 versus control + vehicle and control + DCF), with no significant difference in infarct size between the two preconditioned groups. The incidence of ventricular tachycardia (VT) during the 90 minutes of ischemia was significantly attenuated in both preconditioned groups (p < 0.05 versus controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Deaminase Inhibitors; Animals; Female; Heart Rate; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Necrosis; Pentostatin; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Ventricular Fibrillation

Deoxycoformycin (dCF) is an investigational nucleoside with significant activity in hairy cell leukemia, cutaneous T-cell lymphoma, and chronic lymphocytic leukemia. During a 4-year period, 11 patients have experienced cardiac events as a complication of dCF therapy under NCI sponsorship. The cases are presented and recommendations for the administration of dCF to patients with pre-existing heart disease are made.

Topics: Aged; Arrhythmias, Cardiac; Chest Pain; Electrocardiography; Female; Heart Diseases; Humans; Male; Middle Aged; Myocardial Infarction; Pentostatin