Attenuation of experimental subarachnoid hemorrhage-induced cerebral vasospasm by CGS 26303, an endothelin-converting enzyme inhibitor.
The effect of CGS 26303, an endothelin-converting enzyme inhibitor, on the prevention and reversal of cerebral vasospasm was investigated in a rabbit model of subarachnoid hemorrhage (SAH). In the prevention study, rabbits were injected with 3 ml of autologous blood in the cisterna magna and treatment with CGS 26303 i.v. was initiated 1 h later. The compound was subsequently administered at 12, 24, and 36 h post SAH and animals were sacrificed at 48 h post SAH. Treatment with CGS 26303 at 3, 10, and 30 mg/kg resulted in dose-dependent increases in the concentrations of the compound in cerebrospinal fluid samples, and the arterial narrowing after SAH was significantly attenuated in all three groups. Morphologically, corrugation of the internal elastic lamina of vessels was often observed in the vehicle-treated group, but it was not prominent in the CGS 26303-treated groups and the healthy controls. In the reversal study, treatment with CGS 26303 was initiated 24 h post SAH and a second injection was given 12 h later. Arterial narrowing was significantly attenuated in rabbits treated with CGS 26303 at 30 mg/kg. These results demonstrate that CGS 26303 may be an effective agent in prevention and reversal of cerebral vasospasm after aneurysmal SAH.
Kwan
A L
AL
Department of Neurological Surgery, University of Virginia, Charlottesville, USA.
Bavbek
M
M
Jeng
A Y
AY
Toyoda
T
T
Kassell
N F
NF
Lee
K S
KS
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D000072396:Endothelin-Converting Enzymes; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D011817:Rabbits; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000503:physiopathology*; D013777:Tetrazoles / Q000134:cerebrospinal fluid / Q000627:therapeutic use*
D063065:Organophosphonates; D011480:Protease Inhibitors; D013777:Tetrazoles; C089987:CGS 26303; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes