Arginase inhibition improves coronary microvascular function and reduces infarct size following ischaemia-reperfusion in a rat model

J. Grönros, A. Kiss, M. Palmér, C. Jung, D. Berkowitz, J. Pernow

Research output: Contribution to journalArticle

Abstract

Aim: Ischaemia-reperfusion 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 8 days, were treated with vehicle or the arginase inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA; 100 mg kg-1) intravenously 15 min before ischaemia. Coronary flow velocity was determined repeatedly during reperfusion. Results: Arginase activity in the ischaemic-reperfused myocardium was increased already at 20 min of reperfusion and maintained at 8 days. Infarct size was reduced by arginase inhibition at 2 h (39 ± 3% of the area at risk (AAR) vs. 51 ± 2% in the vehicle group, P < 0.01) and at 8 days 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 24 h 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 8 days after reperfusion. Inhibition of arginase may thus be a promising therapeutic target to prevent the development of microvascular dysfunction and myocardial injury following ischaemia-reperfusion.

Original languageEnglish (US)
Pages (from-to)172-179
Number of pages8
JournalActa Physiologica
Volume208
Issue number2
DOIs
StatePublished - Jun 1 2013

Keywords

  • Arginase
  • Coronary artery
  • Microvascular function
  • Nitric oxide
  • Reperfusion

ASJC Scopus subject areas

  • Physiology

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