Differential effects of a nitric oxide donor on reperfusion-induced microvascular dysfunction in diabetic and non-diabetic rats

Aims/hypothesis. Diabetes is associated with a high incidence of ischaemic disease and impaired nitric oxide responses. Therefore, the aim of the pres ent study was to assess the effect of nitric oxide on ischaemia/reperfusion (I/R)-induced microvascular responses in an experimental model of diabetes . Methods. Leucocyte-endothelial cell interactions were studied in mesenteric venules after superior mesenteric artery occlusion (10 min), at 10 and 30 min of reperfusion in control and streptozotocin-induced diabetic rats. An oxidant-sensitive fluorochrome was used to measure oxidant production durin g reperfusion. P-selectin and ICAM-1 expression were quantified at 10 and 3 0 min of reperfusion respectively, using radiolabelled monoclonal antibodie s. The transcription of ICAM-1 mRNA was determined by northern blot. The ef fect of spermine NONOate, given locally, on all variables studied, was asse ssed in additional experiments. Results. Ischaemia/reperfusion induced an enhanced leucocyte accumulation a nd oxidant production in diabetic animals. Moreover, I/R enhanced endotheli al P-selectin expression in both groups of animals, whereas it only up regu lated ICAM-1 endothelial expression and mRNA expression in diabetic rats. S permine NONOate abrogated to a similar extent leucocyte adhesion and emigra tion in control and diabetic animals, although the mechanisms underlying th is protective effect appear to be different. In control rats Spermine NONOa te effectively prevented P-selectin up regulation, whereas in diabetic rats NO appreciably attenuated the rapid up regulation of ICAM-1 by preventing its transcription. Conclusions/interpretation. Expression of ICAM-1 is rapidly increased in di abetic, but not control, animals exposed to I/R. The increased endothelial cell adhesion molecule expression, leucocyte-endothelial cell adhesion and oxidant stress induced by I/R in diabetic rats are significantly attenuated by exogenous NO.