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{.extbackslash}textpercent 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+/- 3cells/0.1 mm(2) in wildtype rats (mean+/-S.E.M., n{.extbackslash}textequals10-11, P{.extbackslash}textequals0.0093). 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{.extbackslash}textpercent in sl/sl, 51.4+/-0.9{.extbackslash}textpercent in +/+, mean+/-S.E.M., n{.extbackslash}textequals5, P{.extbackslash}textequals0.0560). 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. (C) 2002 Elsevier Science B.V. All rights reserved.