Effects of endothelin-1 and endothelin-A receptor antagonist on recovery after hypothermic cardioplegic ischemia in neonatal lamb hearts.
BACKGROUND
Prior studies suggest an important role for coronary endothelium in ischemia/reperfusion (I/R) injury. Decreased endothelial release of the vasodilator nitric oxide occurs after I/R, but the role of the endothelium-derived vasoconstrictor endothelin-1 (ET-1) in I/R is unknown.


RESULTS
We measured plasma ET-1 concentrations by radioimmunoassay in isolated blood-perfused neonatal lamb hearts before and after 2 hours of 10 degrees C cardioplegic ischemia and examined the effects of ET-1 and the endothelin-A (ET-A) receptor antagonist BE-18257B on the postischemic recovery of isolated hearts. ET-1 levels in coronary sinus blood before ischemia and at 0 and 30 minutes of reperfusion in 8 control hearts were constant (2.2 +/- 1.2 fmol/L, 2.2 +/- 1.3 fmol/L, and 2.5 +/- 1.0 fmol/L, respectively). In group 2 (n = 6), 10 mumol/L of BE-18257B was given just before reperfusion. In group 3 (n = 8), 10 pmol/L ET-1 was given just before the start of reperfusion. At 30 minutes of reperfusion, the ET-A antagonist hearts had significantly greater recovery of LV systolic (positive dP/dt and dP/dt at V10) and diastolic function (negative dP/dt), coronary blood flow (CBF), and MVo2 compared with controls (P < .05). The ET-1 hearts showed significantly reduced recovery of LV systolic (positive maximum and volume-normalized dP/dt) and diastolic (negative maximum dP/dt) function, CBF, and myocardial oxygen consumption compared with controls (P < .05).


CONCLUSIONS
These results, combined with prior studies, suggest that I/R causes reduced production of endogenous vasodilators (eg, nitric oxide), leaving unopposed the vasoconstriction that is caused by the continued presence of ET-1. This imbalance may contribute to I/R injury. ET-A receptor antagonists may be useful therapeutic agents in reducing the injury that results from I/R.
Hiramatsu
T
T
Department of Cardiac Surgery, Children's Hospital, Boston, MA 02115, USA.
Forbess
J
J
Miura
T
T
Roth
S J
SJ
Cioffi
M A
MA
Mayer
J E
JE
D000818:Animals; D001681:Biological Assay; D003326:Coronary Circulation; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006324:Heart Arrest, Induced; D007036:Hypothermia, Induced; D017202:Myocardial Ischemia / Q000503:physiopathology*; D010101:Oxygen Consumption; D010456:Peptides, Cyclic / Q000494:pharmacology; D044022:Receptor, Endothelin A; D012016:Reference Values; D012756:Sheep; D016277:Ventricular Function, Left
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; C069764:cyclo(glutamyl-alanyl-isoleucyl-leucyl-tryptophyl)