Endothelin B receptor deficiency augments neuronal damage upon exposure to hypoxia-ischemia in vivo.
The role of functional endothelin-B (ETB)-receptors on neuronal survival upon hypoxia-ischemia (HI) has been investigated in 14-day-old ETB-receptor-deficient spotting lethal (sl/sl) and wildtype (+/+) rats. Carotid ligation followed by exposure to 8% oxygen for 2 h produced distinct cortical and hippocampal neuronal damage. Damage severity 24 h after HI was mild to intermediate in +/+ rats whereas large cortical infarcts and profound apoptosis of the hippocampus evolved in sl/sl rats. The number of apoptotic cells in the dentate 24 h after HI amounted to 30 +/- 7 cells/0.1 mm(2) in sl/sl compared to 9 +/- 3 cells/0.1 mm(2) in wildtype rats (mean +/- S.E.M., n=10-11, P=0.0093). In-vitro hypoxia (15 h) resulted in a comparable increase in cell death in primary pure neuronal hippocampal cultures from both groups (49.8 +/- 1.6% in sl/sl, 51.4 +/- 0.9% in +/+, mean +/- S.E.M., n=5, P=0.0560). To conclude, absence of functional ETB receptors is associated with an increased susceptibility to HI in-vivo, which is not intrinsic to neurons. Antagonism of ETB receptors seems not to be desirable in ischemic stroke.
Sirén
Anna-Leena
AL
Department of Neurology, Georg-August-University, and Max-Planck-Institute for Experimental Medicine, Hermann-Rein-Strasse 3, D-37075 Göttingen, Germany. siren@em.mpg.de
Lewczuk
Piotr
P
Hasselblatt
Martin
M
Dembowski
Christoph
C
Schilling
Lothar
L
Ehrenreich
Hannelore
H
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000473:pathology; D006624:Hippocampus / Q000503:physiopathology; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000172:deficiency / Q000502:physiology*; D012016:Reference Values
D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin