Endothelin-1 receptor antagonist prevents deterioration of left ventricular function and coronary flow reserve in brain-dead canine heart.
BACKGROUND
Rapid hemodynamic deterioration is caused by induction of brain death, but the exact mechanism is still uncertain. The aim of this study was to investigate the contribution of endothelin-1 by using endothelin-1 receptor antagonist (TAK-044) in a canine brain-death model.


METHODS
Dogs were divided into 2 groups: (1) the TAK group, in which TAK-044 was intravenously injected 30 minutes before brain-death induction at a dose of 3 mg/kg; and (2) the control group. Brain death was induced by rapid inflation of a sub-durally placed balloon catheter. Left ventricular function and coronary flow reserve was compared between the 2 groups.


RESULTS
Brain death caused a transient hyperdynamic response followed by hemodynamic deterioration after 60 minutes in both groups. Left ventricular function, evaluated by the slope of the end-systolic pressure-volume relation was significantly decreased from 7.7 +/- 0.6 to 3.7 +/- 0.3 mm Hg/ml (p < 0.01) in the control group, but was not decreased in the TAK group (7.7 +/- 0.8 to 7.3 +/- 0.9 mm Hg/ml, p = 0.75). Coronary flow reserve, measured by direct injection of acetylcholine (3 microg) into the coronary artery, was significantly reduced at 60 minutes after brain death in the control group (264.8% to 176.6%, p < 0.01), but not in the TAK group (291.2% to 301.3%, p = 0.84). Exactly the same results were obtained when sodium nitroprusside (SNP; 100 microg) was administered.


CONCLUSIONS
TAK-044 can prevent the deterioration of left ventricular function and coronary flow reserve that follows induction of brain death, suggesting that endothelin-1 could play an important role in hemodynamic deterioration by impairment of coronary microcirculation after brain death.
Oishi
Yasuhisa
Y
Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nishimura
Yosuke
Y
Tanoue
Yoshihisa
Y
Kajihara
Noriyoshi
N
Imasaka
Ken-ichi
K
Morita
Shigeki
S
Yasui
Hisataka
H
D000818:Animals; D001926:Brain Death; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D004837:Epinephrine / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000097:blood; D010456:Peptides, Cyclic / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects*
D002317:Cardiovascular Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; C088196:TAK 044; D009638:Norepinephrine; D004837:Epinephrine