Differential effects of a nitric oxide donor on reperfusion-induced microvascular dysfunction in diabetic and non-diabetic rats.
OBJECTIVE
Diabetes is associated with a high incidence of ischaemic disease and impaired nitric oxide responses. Therefore, the aim of the present 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 during reperfusion. P-selectin and ICAM-1 expression were quantified at 10 and 30 min of reperfusion respectively, using radiolabelled monoclonal antibodies. The transcription of ICAM-1 mRNA was determined by northern blot. The effect of spermine NONOate, given locally, on all variables studied, was assessed in additional experiments.


RESULTS
Ischaemia/reperfusion induced an enhanced leucocyte accumulation and oxidant production in diabetic animals. Moreover, I/R enhanced endothelial P-selectin expression in both groups of animals, whereas it only up regulated ICAM-1 endothelial expression and mRNA expression in diabetic rats. Spermine NONOate abrogated to a similar extent leucocyte adhesion and emigration in control and diabetic animals, although the mechanisms underlying this protective effect appear to be different. In control rats Spermine NONOate 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
Expression of ICAM-1 is rapidly increased in diabetic, 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. [Diabetologia (1999) 42: 1350-1358]
Salas
A
A
Department of Gastroenterology, Digestive Diseases Institute, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain.
Panés
J
J
Rosenbloom
C L
CL
Elizalde
J I
JI
Anderson
D C
DC
Granger
D N
DN
Piqué
J M
JM
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007511:Ischemia / Q000150:complications / Q000503:physiopathology*; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009589:Nitrogen Oxides; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000503:physiopathology*; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013152:Splanchnic Circulation / Q000187:drug effects*; D014657:Vasculitis / Q000209:etiology / Q000503:physiopathology; D014699:Venules / Q000187:drug effects / Q000503:physiopathology
D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D018799:Intercellular Adhesion Molecule-1; C091861:spermine nitric oxide complex; D013096:Spermine