(S)-emopamil, a novel calcium and serotonin antagonist for the treatment of cerebrovascular disorders. 3rd communication: effect on postischemic cerebral blood flow and metabolism, and ischemic neuronal cell death.
The effect of (S)-emopamil ((2S)-2-isopropyl-5-(methylphenethylamino)-2-phenylvaleronitril e hydrochloride) treatment on postischemic cerebral blood flow and metabolism was investigated in nitrous oxide anesthetized, artificially ventilated rats. Forebrain ischemia was induced and maintained for 20 min by lowering arterial blood pressure to approximately 40 mmHg and clamping both carotid arteries. Local cerebral blood flow and glucose utilization were evaluated autoradiographically in 34 cerebral regions. In the cerebral blood flow studies intravenous infusion of 0.1 mg/(kg min) (S)-emopamil was begun 5 min after the end of ischemia. Local cerebral blood flow was determined 60 min later using [14C]iodoantipyrine. When the animals were treated with saline only, postischemic blood flow of 22 affected forebrain areas fell on average to 42 +/- 13% of nonischemic control. Treatment with (S)-emopamil increased perfusion of the same areas in a region-dependent fashion by an average of 54 +/- 19%, resulting in 63 +/- 17% of control values. The rise of blood flow in structures not directly affected by ischemia amounted to 52 +/- 27% (134 +/- 23% of control). In the studies on cerebral metabolism, the experimental animals received a total of 6 mg/kg (S)-emopamil by slow intravenous infusion before and during the ischemic episode. Determination of local cerebral glucose utilization was initiated after 50 min of postischemic recirculation using [14C]deoxyglucose. In the placebo-treated experimental group average glucose utilization of 14 forebrain areas was significantly lower (74 +/- 9% of control) than in the nonischemic control group.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Neuropsychopharmacology, Ludwigshafen/Rhein Fed. Rep. of Germany.
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Hofmann
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002545:Brain Ischemia / Q000503:physiopathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D005849:Gerbillinae; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D014700:Verapamil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D002121:Calcium Channel Blockers; D012702:Serotonin Antagonists; D014700:Verapamil; D005947:Glucose; C052752:emopamil