Effects of AE0047 on cerebral ischaemia and oedema after middle cerebral artery occlusion in cats.
1. AE0047 is a new dihydropyridine calcium antagonist with protective effects against cerebral ischaemia and the occurrence of stroke in several animal models. 2. In the present study we investigated whether AE0047 would improve the reduced cerebral blood flow (CBF) and oedema formation in cats subjected to middle cerebral artery (MCA) occlusion and compared it for efficacy with other dihydropyridine calcium antagonists with different moieties, such as nilvadipine and nicardipine. 3. Middle cerebral artery occlusion reduced local CBF (ICBF), as measured by the hydrogen clearance method, while dry weight measurement showed that water content in the cortical tissues surrounding each ICBF measurement electrode had increased after 4 h ischaemia. 4. Both AE0047 (10 micrograms/kg) and nilvadipine (30 micrograms/kg), given intravenously 20 min after MCA occlusion, produced an approximate 10% hypotensive response and significantly increased ICBF in severely and moderately ischaemic regions, grouped according to the initial reduced flow values. However, nicardipine (5 micrograms/kg bolus followed by infusion of 3 micrograms/kg per min for 60 min) failed to mitigate the reduction in ICBF despite an increase in the ICBF of the contralateral cortex. In addition, AE0047 tended to prevent an increase in cortical water content in severely ischaemic regions, whereas water content in both nilvadipine- and nicardipine-treated groups tended to increase. 5. These results suggest that dihydropyridine calcium antagonists act differently on cerebral ischaemia and oedema formation in a manner dependent on their side-chain structures and that AE0047 effectively attenuates ischaemic brain damage without aggravating oedema.
Shinyama
H
H
Pharmacology Laboratories, Green Cross Corporation, Osaka, Japan. shinyama@greencross.co.jp
Hayashi
K
K
Kawamura
T
T
Nakamura
N
N
Kagitani
Y
Y
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001834:Body Water; D002545:Brain Ischemia / Q000188:drug therapy*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D002415:Cats; D002536:Cerebral Arteries; D002540:Cerebral Cortex / Q000098:blood supply; D004095:Dihydropyridines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D012039:Regional Blood Flow / Q000187:drug effects
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C064970:AE0047