Effects of the Ca++-permeable nonselective cation channel blocker LOE 908 on subarachnoid hemorrhage-induced vasospasm in the basilar artery in rabbits.
OBJECTIVE
The Ca++ influx into vascular smooth-muscle cells (VSMCs) plays a fundamental role in the development and chronic effects of vasospasm after subarachnoid hemorrhage (SAH). The Ca++-permeable nonselective cation channels (NSCCs) are activated by several endothelium-derived constricting factors such as endothelin 1 (ET-1) and thromboxane A2. Moreover, the receptor-operated Ca++ channel blocker LOE 908 inhibits ET-1-induced extracellular Ca++ influx via NSCCs in the VSMCs of the basilar artery (BA) and the NSCC-dependent part of ET-1-induced vasoconstriction of BA rings. The purpose of the present study was to evaluate the in vivo role of LOE 908 on SAH-induced vasospasm.


METHODS
Forty-two Japanese white rabbits were assigned to seven groups. Treatment groups consisted of the following: 1) control rabbits without SAH that received a cisternal injection of saline; 2) rabbits with SAH that were subjected to the intravenous administration of saline; 3 through 6) rabbits with SAH that underwent the intravenous administration of 0.01. 0.1, 1, or 10 mg/kg LOE 908, respectively; and 7) rabbits without SAH that underwent the intravenous administration of 10 mg/kg LOE 908. Autologous blood was injected into the cisterna magna. The caliber of the BA was measured on angiographic studies before and after the cisternal injection of autologous blood. The intravenous injection of LOE 908 inhibited the magnitude of an SAH-induced vasosapsm. In addition, the concentration of LOE 908 required to relax vasospasm (1 mg/kg) correlated with that required to block Ca++ influx into VSMCs.


CONCLUSIONS
The Ca++ channel blocker LOE 908 may inhibit the magnitude of an SAH-induced vasospasm by blocking the influx of Ca++ through NSCCs in rabbit BAs. Blocking the NSCCs may represent a new treatment for cerebral vasospasm after SAH.
Kawanabe
Yoshifumi
Y
Department of Neurosurgery and Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan. ykawanabe@rics.bwh.harvard.edu
Masaki
Tomoh
T
Hashimoto
Nobuo
N
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D002412:Cations / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology*; D011817:Rabbits; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D020301:Vasospasm, Intracranial / Q000209:etiology* / Q000517:prevention & control*
D000081:Acetamides; D002412:Cations; D007473:Ion Channels; D007546:Isoquinolines; C081356:LOE 908; D002118:Calcium