PROLONGED EFFECTS OF CHOLINESTERASE INHIBITION WITH EPTASTIGMINE ON THE CEREBRAL BLOOD FLOW-METABOLISM RATIO OF NORMAL RATS

The cerebrovascular and metabolic effects of the novel cholinesterase inhibitor eptastigmine were tested in conscious rats. The drug was adm inistered by single intravenous injection, and blood flow or glucose u tilization were assessed in 38 brain regions by quantitative autoradio graphic techniques. A dose-dependent increase in regional cerebral blo od flow (rCBF) was obtained for i.v. doses ranging from 0.5 to 3 mg kg -1. Forty minutes after the dose of 1.5 mg kg-1, average rCBF of the 3 8 regions studied was (mean +/- SD) 2.62 +/- 0.62 ml g-1 min-1, a valu e significantly higher than that of saline-injected controls (1.46 +/- 0.26; p < 0.005). In contrast, a similar dose of eptastigmine did not significantly alter regional cerebral glucose utilization (rCGU) (0.9 0 +/- 0.21 mumol g-1 min-1) when compared with saline-injected control s (0.99 +/- 0.08 mumol g-1 min-1). A linear correlation between rCBF a nd rCGU was observed both in saline (r = 0.871) and eptastigmine (r = 0.873)-injected animals but the slope of the regression line of rCBF o n rCGU was significantly higher (p < 0.01) in the eptastigmine group ( 2.863 +/- 0.266) than in the controls that received saline (1.00 +/- 0 .094). The cerebral vasodilatation induced by eptastigmine peaked at 4 0 min after drug administration. No toxic signs were observed at the d oses used. Mean arterial blood pressure decreased after 0.5 mg kg-1 (c ontrol = 109.3 +/- 10.56 mm Hg; eptastigmine = 96.6 +/- 8.10 mm Hg) bu t did not differ from control at the higher doses. It is concluded tha t eptastigmine induces a long-lasting increase in rCBF and a significa nt enhancement of the rCBF:rCGU ratio in most regions. The results sug gest an important role of endogenous acetylcholine in the control of c erebral perfusion.