Effect of adenosine deaminase inhibition with pentostatin on myocardial stunning in dogs.
Pentostatin (2-deoxycoformycin) is a potent inhibitor of adenosine deaminase and has been demonstrated to augment endogenous adenosine levels during regional and global myocardial ischemia. Based on the rationale that increasing endogenous adenosine during ischemia may be cardioprotective, the objective of this study was to determine if adenosine deaminase inhibition with pentostatin could improve postischemic contractile dysfunction (stunning) in open-chest anesthetized dogs. All animals underwent 15 min of coronary occlusion followed by 3 h of reperfusion preceded by an intravenous bolus of either 0.2 mg/kg of pentostatin (n = 8) or saline (n = 7). Sonomicrometers were placed in the ischemic area and were used to measure systolic wall thickening before, during, and after occlusion of the left anterior descending artery. Myocardial blood flow was measured with tracer labeled microspheres at baseline, 10 min of occlusion and at 1 h of reperfusion. Both groups were equally dyskinetic during occlusion (-21 +/- 5% of baseline thickening in the controls and -28 +/- 8% in the pentostatin group). The pentostatin group, however, demonstrated better contractile function at all time points during reperfusion, which was significantly different from the control group at 3 h of reperfusion. The improvement in regional function in the pentostatin group was not due to significant disparities in hemodynamic variables, size of the region at risk, or in collateral blood flow. These results indicate that pentostatin can ameliorate the severity of myocardial stunning, an effect we propose is due to increasing endogenous levels of adenosine during the ischemic interval. Although significant improvement was detected with pentostatin, the improvement was modest compared to controls, suggesting that the utility of inhibiting adenosine deaminase to modify regional mechanical stunning is limited.
McClanahan
T B
TB
Cardiovascular Therapeutics Section, Parke-Davis Pharmaceutical, Ann Arbor, Michigan 48103, USA.
Ignasiak
D P
DP
Martin
B J
BJ
Mertz
T E
TE
Gallagher
K P
KP
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D004285:Dogs; D005260:Female; D008297:Male; D009200:Myocardial Contraction; D017682:Myocardial Stunning / Q000473:pathology / Q000517:prevention & control*; D015649:Pentostatin / Q000494:pharmacology*
D058892:Adenosine Deaminase Inhibitors; D015649:Pentostatin