Effect of adenosine deaminase inhibition with pentostatin on myocardial stunning in dogs

Abstract

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.

Adenosine-mediated cardioprotection in the aging myocardium

“…Adenosinergic cardioprotection in ischemic-reperfused hearts involves reductions in oncotic [41][42][43][44][45] and apoptotic death [46], and improved functional outcomes [28][29][30][31][32]37,43]. Whether ARs specifically protect against reversible injury is difficult to ascertain, although AR agonism enhances post-ischemic contractility in models with minimal irreversible injury [37,43,[47][48][49]. Recent work supports differential effects of acute adenosine [41,50] vs. transient adenosinergic preconditioning [51], consistent with multiple pathways of protection.…”

“…Bolling et al [102] first presented the notion of adenosine protecting the heart as bsubstrateQ (for nucleotide pool repletion) vs. bsignalQ (via AR activity). Manipulation of nucleotide repletion and adenosine handling enhances ischemic tolerance in mature hearts [40,41,48,102], and protection with adenosine is reduced by adenosine kinase inhibition, confirming a role for phosphorylation [41]. In preliminary studies we have shown that treatment with adenosine deaminase or kinase inhibitors fails to modify ischemic tolerance in aged hearts [103].…”

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

“…Moreover, protective effects of adenosine are limited by blockade of adenosine kinase, supporting a role for phosphorylation in cardioprotection with adenosine itself (228). Inhibition of adenosine deamination has been known for some time to also enhance ischemic tolerance (58, 130,200,315). The latter response has been attributed to reduced generation of xanthine oxidase-derived radicals (301) or enhanced purine salvage (27, 130).…”

“…From the relative effects of adenosine receptor antagonism and adenosine kinase inhibition, the major proportion of protection with adenosine is receptor mediated, with a lesser but still significant contribution from adenosine phosphorylation (228). When deamination is blocked, the net result is a similar degree of cardioprotection as that observed with adenosine kinase blockade (58, 130,200,227,315). However, when both processes are simultaneously inhibited, effectively trapping formed adenosine, postischemic recovery is impaired (227).…”

“…In this situation, a reduction in irreversible injury will impact on conventional measures of stunning (myocardial contractility and arrhythmogenesis). Nonetheless, postischemic contractility is enhanced by exogenous and endogenous adenosinergic stimuli under conditions of limited or no detectable cell death (149,161,165,200,201,210,215,234,235,246,258,318). In addition, recent work has identified differential effects of adenosine (77,228) and adenosinergic preconditioning (226) on oncosis versus contractile function, supporting amelioration of both injuries via different pathways.…”