Chronic inhibition of rho‐kinase augments contractions in diabetes

Abstract

Objective: Acute inhibition of rho‐kinase decreases augmented contractions of arteries in diabetic animals. The objective of this study was to determine if chronic inhibition of rho‐kinase with fasudil would prevent enhanced contractions of arteries from diabetic mice.Methods: Non‐diabetic (ND) and streptozotocin‐induced diabetic (D) male mice (Strep 100–150 mg/kg ip) were treated with fasudil (100mg/kg/day) in their drinking water for 12–14 weeks. Responses of isolated aortic rings to serotonin (5HT, 0.01–10 microM), thromboxane mimetic U46619 (0.01–1 microM), KCl (25–75 mM), and acetylcholine (Ach, 0.1–10 microM) were compared to age‐matched untreated ND and D mice.Results: Fasudil had no effect on weights or glucose levels of ND (mg/dl minus fasudil 213±10; plus fasudil 200±8) or D mice (mg/dl minus fasudil 428±56; plus fasudil 458±55). 5HT, U46619 and KCl produced concentration‐dependent contractions of aorta from ND. Contractions to 5HT and KCl but not U46619 were increased in D arteries compared to ND. Surprisingly, fasudil increased contractions to 5HT and KCl in ND and D. Relaxation to ACh was not altered in D but was decreased similarly in both ND and D by fasudil.Conclusion: We conclude that chronic fasudil does not protect arteries of diabetic mice from development of abnormal vasoconstriction.This study was supported by grants from the Dept of Veterans Affairs and American Diabetes Association.