title: Effects of endothelin-1 and L-arginine after cold ischemia in lamb hearts.
abstract: BACKGROUND
  Prior studies from our laboratory have suggested an important role for the coronary endothelium in the injury resulting from hypothermic ischemia and reperfusion. A decreased endothelial response to intraarterial acetylcholine occurs after ischemia/reperfusion, implying a reduced release of the vasodilator nitric oxide by endothelial cells, but the role of endothelial-derived vasoconstrictor endothelin-1 in ischemia/reperfusion and interactions between endothelin-1 and nitric oxide in ischemia/reperfusion are still unclear.
  
  
  METHODS
  We examined the effects of endothelin-1 and L-arginine, the precursor for nitric oxide, on functional recovery of isolated, blood-perfused neonatal lamb hearts undergoing 2 hours of ischemia at 10 degrees C. One group (n = 8) received 10 pmol/L endothelin-1 before reperfusion, and a second group (n = 8) received a continuous infusion of 3 mmol/L L-arginine during the initial 20 minutes of reperfusion. The third group (n = 8) received both endothelin-1 and L-arginine in the same way as in the endothelin-1 and L-arginine groups. The fourth group underwent the same period of hypothermic ischemia without interventions during reperfusion.
  
  
  RESULTS
  After 30 minutes of reperfusion, the endothelin-1-treated hearts showed significantly reduced recovery of left ventricular systolic function (positive maximum dP/dt and volume normalized [V10] dP/dt) and diastolic function (negative maximum dP/dt), coronary blood flow, and myocardial oxygen consumption compared with the control group (p < 0.05). These effects of endothelin-1 were offset to equal the values observed in controls having unmodified reperfusion by adding L-arginine. The L-arginine group had significantly greater recovery of left ventricular systolic function (positive maximum dP/dt, maximum developed pressure, dP/dt at V10, and developed pressure at V10) and diastolic function (negative maximum dP/dt), coronary blood flow, and myocardial oxygen consumption compared with the control group (p < 0.05).
  
  
  CONCLUSIONS
  These results, combined with our previous observations that endothelin-1 levels are unchanged by hypothermic ischemia and reperfusion, suggest that there is an imbalance between the endothelial production of endothelin-1 and nitric oxide, which affects postischemic coronary blood flow and the recovery of ventricular function. Interventions that modify this imbalance of endothelially derived substances could favorably influence the outcome after a period of hypothermic ischemia and reperfusion.
authors.affiliation: Department of Cardiac Surgery and Cardiology, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hiramatsu
authors.forename: J M
authors.initials: JM
authors.lastname: Forbess
authors.forename: T
authors.initials: T
authors.lastname: Miura
authors.forename: S J
authors.initials: SJ
authors.lastname: Roth
authors.forename: M A
authors.initials: MA
authors.lastname: Cioffi
authors.forename: J E
authors.initials: JE
authors.lastname: Mayer
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D016232:Endothelins / Q000494:pharmacology*; D007036:Hypothermia, Induced; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D010101:Oxygen Consumption; D012756:Sheep; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D016232:Endothelins; D009569:Nitric Oxide; D001120:Arginine