Role of eicosanoids, NO and PDE5 in the changes in vascular reactivity to acetylcholine (Ach) and phenylephrine (PE) in rats with diabetes mellitus (DM)

Abstract

We previously showed that aortic rings from rats with 2‐weeks DM had an enhanced relaxant response to Ach or DMPPO (PDE5 inhibitor) and a lower contractile response to PE compared with controls. We used indomethacin (INDO) and L‐NAME and measured aortic PDE5 activity to explore the role of eicosanoids, NO and PDE 5 in these changes in streptozotocin‐induced DM. INDO enhanced relaxation by Ach in the control (C) group but had no influence in the DM group, and the response to Ach became similar in the 2 groups. L‐NAME abolished Ach‐induced relaxation in both groups, but C rings had a significant contractile response, not seen in DM rings. When both L‐NAME and INDO were used, the responses to Ach became identical. PE induced contraction was depressed in DM rings. L‐NAME enhanced PE‐induced contraction in both groups but did not eliminate the difference. INDO reduced the response to PE in C but not DM rings, and the difference between them was abolished. The relaxant response to DMPPO was greater in DM rings. INDO reduced the response to DMPPO in DM and slightly enhanced it in C, thus abolishing the difference between them. L‐NAME also abolished the difference but not the vasodilation in response to DMPPO. There was no change in total cGMP hydrolysis or PDE5 activity but an increased total cAMP hydrolysis and PDE 4 activity in DM aorta. The results suggest that there is a reduced production of a constrictor prostanoid in DM that causes greater relaxation to Ach and lower contraction to PE. DMPPO acts by mechanisms other than PDE5 inhibition and accumulation of cGMP; a possible effect on PDE4 may explain its interaction with INDO.