The effects of zenarestat, an aldose reductase inhibitor, on minimal F-wave latency and nerve blood flow in streptozotocin-induced diabetic rats.
The effects of zenarestat, 3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid, an aldose reductase inhibitor (ARI), on F-wave conduction abnormalities, nerve blood flow (NBF) reduction and sorbitol accumulation were studied in streptozotocin-induced diabetic rats. Two weeks after the induction of diabetes, zenarestat was given once a day for two weeks. In diabetic control rats, marked accumulation of sorbitol, reduction of NBF and prolongation of minimal F-wave latency (FWL) were observed as compared to normal rats. Zenarestat, at a dose of 32 mg/kg, inhibited sorbitol concentration to nearly the normal rat level and significantly improved not only NBF but also minimal FWL. At a dose of 3.2 mg/kg, sorbitol accumulation was inhibited by approximately 40% and there was a tendency to increase in NBF; however, minimal FWL was not improved at all. These data suggest that a highly inhibition of the nerve sorbitol accumulation is requisite for the treatment of diabetic peripheral neuropathy.
Yamamoto
T
T
Department of Metabolic Diseases, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Takakura
S
S
Kawamura
I
I
Seki
J
J
Goto
T
T
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009431:Neural Conduction / Q000187:drug effects* / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects*; D012584:Sciatic Nerve / Q000098:blood supply*; D013311:Streptozocin
D004791:Enzyme Inhibitors; D011799:Quinazolines; C064920:FR 74366; D013311:Streptozocin; D000449:Aldehyde Reductase