Effects of ponalrestat on depressor responses to arachidonic acid in streptozotocin-diabetic rats

1. This study measured reductions in diastolic blood pressure to arachidonic acid (AA, 0.125-2.0 mg/kg i.v.) in 14-day streptozotocin-diabetic (60 mg/kg i.v.) and control rats anaesthetized with pentobarbitone (50-70 mg/kg i.p.) having been treated acutely or chronically with saline or ponalrestat (25 mg/kg p.o. 1 hr prior to anaesthesia, or 25 mg/kg p.o. daily for 14 days). 2. Streptozotocin-treated diabetic rats displayed reduced sensitivity to depressor effects of AA (0.125-2.0 mg/kg) when compared with controls. 3. Acute treatment with ponalrestat did not change responses to AA in controls or diabetics, whereas chronic treatment resulted in a small increase in depressor responses to AA (0.125, 0.25 and 2.0 mg/kg) in diabetics but not controls. 4. The mechanism of this action of ponalrestat remains to be elucidated, although the results are compatible with the hypothesis that increased polyol pathway activity may affect responses to, or metabolism of eicosanoids.