A New Cardioprotective Strategy to Salvage Myocardium from Reperfusion Injury: Combination PAR1 Inhibition and PAR2 Activation at Reperfusion

Abstract

Protease activated receptors (PAR) play contrasting roles in ischemic‐reperfusion: PAR1 activation is deleterious while PAR2 activation may exert protection. This study tested the hypothesis that the combination of PAR1 inhibition and PAR2 activation exerts enhanced cardioprotection. Methods: In open‐chest rats, the left coronary artery was occluded for 30 min and reperfused for 3 hours. Rats were randomly assigned to: 1) Control: saline 1 ml/Kg; 2) PAR1 antagonist BMS 200261 1mg/Kg; 3) PAR2 agonist peptide (PAR2 AP) SLIGRL‐NH2 1 mg/Kg; 4) BMS 200261 + PAR2 AP: each 1mg/Kg. All drugs were given 5 min before reperfusion. Results: Area at risk (33%‐38%) was comparable. Compared to control, infarct size was significantly reduced in both BMS 200261 and PAR2 AP groups (40.7 ?2.7* and 37.2 ?2.3* vs 55.8 ?2.4). The combination of BMS 200261 and PAR2 AP further reduced infarct size (28.0 ?3.6*?). Conclusions: 1) Either inhibition of PAR1 or activation of PAR2 specifically at reperfusion is cardioprotective in vivo; 2) the combination of the two approaches is significantly more effective in reducing infarct size. * P < 0.05 vs. control. ?P < 0.05 vs. PAR 2 AP or BMS group.