The effects of LY393613, nimodipine and verapamil, in focal cerebral ischaemia.
This study evaluates the effects of N-(2-[bis (4-fluorophenyl)methoxy]ethyl)-1-butanamine hydrochloride (LY393613), a novel neuronal (N/P/Q-type) Ca(2+) channel blocker, in ischaemia. For comparison, two commonly used L-type Ca(2+) channel blockers; nimodipine and verapamil were also evaluated. Ischaemia was induced in freely moving rats by micro-injection of endothelin-1 near the middle cerebral artery. In vivo microdialysis, laser Doppler flowmetry and histology were used to monitor ischaemia. Administration of LY393613, before and after the insult, attenuated the ischaemia-induced glutamate release, but not the dopamine release. Both nimodipine and verapamil failed to affect transmitter releases significantly, when administered post-occlusion. None of the compounds tested, produced any significant change in striatal blood flow. Histology showed that ischaemic damage was significantly less in LY393613 pre-treated rats. In conclusion, LY393613, a neuronal N/P/Q-Ca(2+) channel blocker, can attenuate ischaemic brain damage. The protective mechanism appears to be mainly the attenuation of the ischaemia-induced glutamate release, rather than its effect on cerebral hemodynamics.
Bogaert
L
L
Department of Pharmaceutical Chemistry and Drug Analysis, Pharmaceutical Institute, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
O'Neill
M J
MJ
Moonen
J
J
Sarre
S
S
Smolders
I
I
Ebinger
G
G
Michotte
Y
Y
D000588:Amines / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D002073:Butanes / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D019332:Endothelin-1 / Q000008:administration & dosage; D018698:Glutamic Acid / Q000378:metabolism; D017078:Laser-Doppler Flowmetry; D008297:Male; D017551:Microdialysis; D009553:Nimodipine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D000588:Amines; D002073:Butanes; D002121:Calcium Channel Blockers; D019332:Endothelin-1; C419623:LY 393613; D018698:Glutamic Acid; D009553:Nimodipine; D014700:Verapamil; D004298:Dopamine