Arginase inhibition improves coronary microvascular function and reduces infarct size following ischaemiareperfusion in a rat model

Aim Ischaemiareperfusion injury is associated with reduced bioavailability of nitric oxide (NO) and microvascular dysfunction. One emerging mechanism behind reduced NO bioavailability is upregulation of arginase, which metabolizes the NO synthase substrate l-arginine. This study investigated the effects of arginase inhibition on coronary flow velocity and infarct size during reperfusion. Methods Anaesthetized rats, subjected to 30-min coronary artery ligation and reperfusion up to 8days, were treated with vehicle or the arginase inhibitor N-hydroxy-nor-l-arginine (nor-NOHA; 100mgkg1) intravenously 15min before ischaemia. Coronary flow velocity was determined repeatedly during reperfusion. Results Arginase activity in the ischaemic-reperfused myocardium was increased already at 20min of reperfusion and maintained at 8days. Infarct size was reduced by arginase inhibition at 2h (39 +/- 3% of the area at risk (AAR) vs. 51 +/- 2% in the vehicle group, P<0.01) and at 8days of reperfusion (13 +/- 2% of the left ventricle (LV) vs. 22 +/- 2%, P<0.05). Basal coronary flow velocity was higher during reperfusion in the group given nor-NOHA, and it correlated inversely to infarct size (P<0.01, r=0.60). Hyperaemic coronary flow velocity was also increased in the nor-NOHA-treated group compared to vehicle at 24h and at day 8 (P<0.05). Conclusion It is concluded that arginase activity is increased already during early reperfusion. Arginase inhibition increases coronary flow velocity and reduces infarct size that is sustained 8days after reperfusion. Inhibition of arginase may thus be a promising therapeutic target to prevent the development of microvascular dysfunction and myocardial injury following ischaemiareperfusion.