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, uorobenzothiazol-2-yl)methyl]-5-methylphenylacetic acid} on the sciatic nerve blond flow in streptozotocin-induced diabetic rats were examined. Blood flow was analyzed in terms of mass, i.e. the volume o f blood in tissue, and of velocity, i,e. the velocity of the blood flo w. 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 d ose of 30 mg/kg per day for 4 consecutive weeks following a 3-week per iod without treatment ameliorated the reduced blood flow by 51%, and w as accompanied by a recovery of velocity. The increase in the range of blood mass values was reversed by treatment with GP-1447. The restora tion of the range oi blood mass values, but not that of the blood flow , by GP-1447 was blocked by treatment with the nitric oxide (NO) synth ase inhibitor, N-G-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 flo w is involved in the restoration of decreased MCV ill diabetes. It wou ld appear that GP-1447-induced amelioration of neurovascular defects i s not mediated solely by the improvement of the NO system, (C) 1998 El sevier Science Ireland Ltd. All rights reserved.