Protective effects of benidipine on arachidonic acid-induced acute cerebral ischemia in rats.
Acute cerebral ischemia was produced in rats by injection of arachidonic acid (AA) into the internal carotid artery. Evans blue (EB) was intravenously injected and its extravasation into the brain was determined as an indicator of disturbances in the blood-brain barrier and endothelial cells. Control animals showed severe cerebral edema and marked blue staining of the brain. Benidipine (30 micrograms/kg, i.p.) suppressed the increase in cerebral water content and the extravasation of EB. Similarly nicardipine (100 micrograms/kg, i.p.) suppressed the elevation of water content and the extravasation of EB. Furthermore, both benidipine (30 micrograms/kg, i.p.) and nicardipine (100 micrograms/kg, i.p.) improved the neuronal injuries following AA-injection. An antiplatelet agent, ticlopidine (100 mg/kg, i.p.), and a thromboxane A2 synthetase inhibitor, OKY-1581 (3 mg/kg, i.p.), also suppressed the elevation of cerebral water content. A lipoxygenase inhibitor, AA-561 (200 mg/kg, p.o.), and a cyclooxygenase inhibitor, indomethacin (10 mg/kg, i.p.), did not prevent the increase in cerebral water content. Neither benidipine (3-30 micrograms/kg, i.v.) nor nicardipine (100 micrograms/kg, i.v.) inhibited the AgNO3-induced thrombus formation of the abdominal aorta, whereas ticlopidine (100 mg/kg, p.o.) and OKY-1581 (3 mg/kg, i.v.) prevented the thrombus formation. From the present results, it is suggested that benidipine, as well as nicardipine, may protect against AA-induced acute cerebral infarction via a mechanism independent of antithrombotic action.
Shirakura
S
S
Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Sano
J
J
Karasawa
A
A
Kubo
K
K
D000818:Animals; D016718:Arachidonic Acid / Q000633:toxicity*; D016227:Benzoquinones / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001929:Brain Edema / Q000517:prevention & control; D002545:Brain Ischemia / Q000139:chemically induced / Q000188:drug therapy*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002544:Cerebral Infarction / Q000139:chemically induced / Q000188:drug therapy*; D004095:Dihydropyridines / Q000494:pharmacology*; D005070:Evans Blue / Q000737:chemistry; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D009529:Nicardipine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013988:Ticlopidine / Q000494:pharmacology
D016227:Benzoquinones; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D016859:Lipoxygenase Inhibitors; D008689:Methacrylates; D016718:Arachidonic Acid; D005070:Evans Blue; C061004:benidipine; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D009529:Nicardipine; D013930:Thromboxane-A Synthase; D013988:Ticlopidine