Enalapril increases the local extravasation of macromolecules and nitric oxide synthase in pancreas of the fructose-fed insulin-resistant rat model.
OBJECTIVE
Angiotensin-converting enzyme (ACE) inhibitors have been associated with an increased risk of acute pancreatitis. The pathogenesis of this condition remains unclear, but an activation of the kinin system and a resultant localized angioedema have been implicated in the initial step leading to acute pancreatic damage. The goal of the present study was to explore the impact of ACE inhibition on pancreatic microcirculation and capillary permeability in normal and insulin-resistant rats.


METHODS
Chow- or fructose-fed Sprague-Dawley rats were treated with enalapril (dosage, 10 mg.kg.d) or vehicle for 4 weeks before measuring in vivo the extravasation of Evans blue (EB) dye in pancreas. Unanesthetized animals (n = 10-17 per group) were injected with EB 20 mg.kg in the caudal vein 10 minutes before killing, and EB dye was extracted from each pancreas by using formamide.


RESULTS
Relative to controls, enalapril-treated animals showed a 5-fold increase in pancreatic extravasation of EB in the fructose-fed rat model (P < 0.001); smaller changes (2-fold) were observed in the chow-fed animals treated with enalapril (P < 0.001). The increase in pancreatic vasopermeability observed with enalapril in the fructose-fed animals was accompanied by a significant increase in total pancreatic nitric oxide synthase (NOS) activity compared to controls (Delta = +128%; P < 0.001). This increase in NOS activity seemed to be solely attributable to an upregulation of the endothelial NOS isoform because only the eNOS immunoreactive mass (as opposed to nNOS) seemed to be increased in the pancreas of these animals. Treatment with enalapril was not associated with any increase in serum amylase concentrations in either animal subgroup.


CONCLUSIONS
Enalapril increases capillary permeability (extravasation of macromolecules) in the pancreas of the fructose-fed rat model. This suggests that ACE inhibition upregulates the eNOS isoform locally, increases vasopermeability of the pancreas, and can therefore result in local edema in the fructose-fed insulin-resistant rat model.
Bouffard
Lucie
L
Department of Medicine, Division of Endocrinology & Metabolism, Université de Sherbrooke, Quebec, Canada.
Papirakis
Marie-Eve
ME
Maheux
Pierre
P
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects*; D004040:Dietary Carbohydrates; D004195:Disease Models, Animal; D004656:Enalapril / Q000494:pharmacology*; D005070:Evans Blue; D005632:Fructose; D007202:Indicators and Reagents; D007333:Insulin Resistance; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D010179:Pancreas / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000806:Angiotensin-Converting Enzyme Inhibitors; D004040:Dietary Carbohydrates; D007202:Indicators and Reagents; D005632:Fructose; D005070:Evans Blue; D004656:Enalapril; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat