Cardioprotective effects of citrulline in ischemia/reperfusion injury via a non-nitric oxide-mediated mechanism

Methods Find Exp Clin Pharmacol. 2000 Sep;22(7):563-71.


The effects of L-citrulline, the byproduct of nitric oxide (NO) synthesis, and its stereoisomer D-citrulline were studied in a polymorphonuclear leukocyte (PMN)-dependent isolated perfused rat heart model consisting of 20 min of global ischemia and 45 min of reperfusion. Ischemic hearts reperfused with either D- or L-citrulline (20 nM) exhibited a marked preservation of left ventricular developed pressure and of maximal rate of development of left ventricular developed pressure, compared to hearts perfused without either D- or L-citrulline (both p < 0.001). In addition, both D- and L-citrulline significantly attenuated PMN accumulation in the post-reperfused myocardium from 288 +/- 33 PMNs/mm2 in untreated hearts to 89 +/- 10 and 76 +/- 6 PMNs/mm2, respectively (both p < 0.001). In isolated rat aortic rings, neither D- or L-citrulline induced any vasodilation or release of nitric oxide from the vascular endothelium. However, expression of P-selectin on the coronary vascular endothelium was markedly attenuated in hearts perfused with either D- or L-citrulline compared to ischemic-reperfused hearts without citrulline (both p < 0.001). These results provide evidence that D- or L-citrulline significantly attenuates PMN-induced cardiac contractile dysfunction in the isolated perfused rat heart subjected to ischemia/reperfusion via a non-NO-mediated mechanism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cardiovascular Agents / therapeutic use*
  • Citrulline / therapeutic use*
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Male
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardial Reperfusion Injury / metabolism
  • Neutrophils / drug effects*
  • Neutrophils / metabolism
  • Nitric Oxide / metabolism
  • P-Selectin / drug effects*
  • P-Selectin / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Ventricular Function, Left / drug effects
  • Ventricular Function, Left / physiology


  • Cardiovascular Agents
  • P-Selectin
  • Citrulline
  • Nitric Oxide