Attenuation of experimental subarachnoid hemorrhage-induced increases in circulating intercellular adhesion molecule-1 and cerebral vasospasm by the endothelin-converting enzyme inhibitor CGS 26303.
OBJECTIVE
Adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, are important mediators of inflammation, and their levels are elevated in the serum of patients following aneurysmal subarachnoid hemorrhage (SAH). The investigators previously found that CGS 26303 is effective in preventing and reversing arterial narrowing in a rabbit model of SAH. The purpose of the present study was to examine whether levels of adhesion molecules are altered after treatment with CGS 26303 in this animal model.


METHODS
New Zealand White rabbits were each injected with 3 ml of autologous blood in the cisterna magna, and intravenous treatment with CGS 26303 (30 mg/kg) was initiated 1 hour later. The compound was subsequently administered at 12, 24, and 36 hours post-SAH. Blood samples were collected at 48 hours post-SAH to measure ICAM-1, VCAM-1, and E-selectin levels. After the rabbits had been killed by perfusion-fixation, the basilar arteries (BAs) were removed and sliced, and their cross-sectional areas were measured. Treatment with CGS 26303 attenuated arterial narrowing after SAH. Morphologically, corrugation of the internal elastic lamina of BAs was prominently observed in the SAH only and vehicle-treated SAH groups, but not in the CGS 26303-treated SAH group or in healthy controls. There were no significant differences in the levels of VCAM-1 among the four groups. The levels of E-selectin were increased in all animals subjected to SAH (those in the SAH only, SAH plus vehicle, and SAH plus CGS 26303 groups) compared with healthy controls (no SAH); however, the levels of ICAM-1 in the SAH only and SAH plus vehicle groups were significantly elevated (p < 0.001), and treatment with CGS 26303 reduced ICAM-1 to control levels following SAH.


CONCLUSIONS
These results show that ICAM-1 may play a role in mediating SAH-induced vasospasm and that a reduction of ICAM-1 levels after SAH may partly contribute to the antispastic effect of CGS 26303.
Lin
Chih-Lung
CL
Department of Neurosurgery, Kaohsiung Medical University, Kaohsiung, Taiwan.
Kwan
Aij-Lie
AL
Dumont
Aaron S
AS
Su
Yu-Feng
YF
Kassell
Neal F
NF
Wang
Chih-Jen
CJ
Wu
Shu-Chuan
SC
Kuo
Ching-Ling
CL
Huang
Ching-Shan
CS
Jeng
Arco Y
AY
Liu
Chin-San
CS
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D019040:E-Selectin / Q000097:blood; D000072396:Endothelin-Converting Enzymes; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000627:therapeutic use*; D011817:Rabbits; D013345:Subarachnoid Hemorrhage / Q000097:blood* / Q000150:complications*; D013777:Tetrazoles / Q000627:therapeutic use*; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D020301:Vasospasm, Intracranial / Q000097:blood / Q000209:etiology / Q000517:prevention & control*
D019040:E-Selectin; D063065:Organophosphonates; D013777:Tetrazoles; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C089987:CGS 26303; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes