Received for publication May 17, 2007.
Revised September 6, 2007.
Accepted for publication September 7, 2007.

P2 Purinoceptor-Mediated Cardioprotection in Ischemic-Reperfused Mouse Heart

Abstract

P2 purinoceptor modulation of injury during ischemia-reperfusion was studied in murine hearts. Effects of P2 agonism or antagonism, and interstitial accumulation of P2 agonists (UTP, ATP, ADP), were assessed in Langendorff perfused hearts during 20 min ischemia and 45 min reperfusion. In control hearts ventricular pressure development recovered to 68±4 mmHg (63±3% of baseline), diastolic pressure remained elevated (23±2 mmHg), and 26±4 U/g lactate dehydrogenase (LDH) was released during reperfusion, evidencing necrosis. Treatment with 250 nM UTP improved pressure development (85±5 mmHg, or 77±2%), and reduced diastolic contracture (by ~70%, to 7±1 mmHg) and LDH loss (by ~60%, to 11±2 U/g). In contrast, P2Y₁ agonism with 50 nM 2-methyl-thio-ATP (2-MeSATP) was ineffective. In the presence of the P2Y antagonist suramin (10 or 200 µM), UTP no longer improved post-ischemic outcomes. Ischemia also substantially elevated interstitial [UTP], [ATP] and [ADP], potentially activating P2 receptors. This was supported in part by effects of antagonists: 200 µM suramin worsened LDH efflux (53±9 IU/g) and contractile dysfunction (41±2 mmHg diastolic pressure; 28±3 mmHg developed pressure), as did P2Y antagonism with either 10 or 100 µM reactive blue 2 (RB-2). However, a 10 µM concentration of suramin failed to alter outcome. P2X antagonism with 10 µM pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid (PPADS) and P2X₁ selective MRS2159 (30 µM) was ineffective. Data collectively support cardioprotection with low concentrations of UTP, and are consistent with P2Y₂ involvement. Endogenous nucleotides may also play a protective role, as evidenced by effects of P2 antagonists, though this warrants further investigation.

Key words: Cardioprotection, Contractile Dysfunction, Ischemia-Reperfusion, Microdialysis, P2 Purinoceptors, UTP

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