Amelioration of neurovascular deficits in diabetic rats by a novel aldose reductase inhibitor, GP-1447: minor contribution of nitric oxide.
The effects of a novel potent aldose reductase inhibitor, GP-1447 [3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-methylphenylace tic acid] on the sciatic nerve blood flow in streptozotocin-induced diabetic rats were examined. Blood flow was analyzed in terms of mass, i.e. the volume of blood in tissue, and of velocity, i.e. the velocity of the blood flow. In diabetic rats, a 63% decrease in blood flow due to a decrease in velocity was observed. The blood mass in the same animals fluctuated, thereby increasing its range of values. Treatment with GP-1447 at a dose of 30 mg/kg per day for 4 consecutive weeks following a 3-week period without treatment ameliorated the reduced blood flow by 51%, and was accompanied by a recovery of velocity. The increase in the range of blood mass values was reversed by treatment with GP-1447. The restoration of the range of blood mass values, but not that of the blood flow, by GP-1447 was blocked by treatment with the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine. Motor nerve conduction velocity (MCV) changes in parallel with blood flow values, while it is inversely proportionate to alterations in the range of blood mass values. It is suggested that the observed beneficial effect of GP-1447 on blood flow is involved in the restoration of decreased MCV in diabetes. It would appear that GP-1447-induced amelioration of neurovascular defects is not mediated solely by the improvement of the NO system.
Pharmacological Research Laboratory, Grelan Pharmaceutical Co. Ltd., Tokyo, Japan.
M
M
Yoshida
Y
Y
Sugiyama
N
N
Akaike
N
N
Ashizawa
T
T
Aotsuka
S
S
Ohbayashi
A
A
Matsuura
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy; D003929:Diabetic Neuropathies / Q000188:drug therapy; D004907:Erythrocyte Deformability / Q000187:drug effects; D008297:Male; D009046:Motor Neurons / Q000187:drug effects; D009431:Neural Conduction / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010648:Phenylacetates / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000098:blood supply*; D013012:Sorbitol / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
D001786:Blood Glucose; C106125:GP 1447; D010648:Phenylacetates; D013844:Thiazoles; D019335:Nitroarginine; D009569:Nitric Oxide; D013012:Sorbitol; D000449:Aldehyde Reductase; D019001:Nitric Oxide Synthase