Microvascular permeability with sulfonylureas in normal and diabetic hamsters

Abstract

The hamster cheek pouch is an experimental model in which quantitative studies of macromolecular permeability can be made by direct observation of extravasated fluorescein isothiocyanate (FITC)-dextran (leaks). The advantage of this model is that simultaneous light and fluorescent-light microscopy observations can be performed with instantaneous correlations between the site of FITC-dextran extravasation and the vessel morphology. The aims of our study were to compare, using the cheek pouch preparation, the effects of two sulfonylureas, gliclazide and glibenclamide, on the macromolecular permeability increase induced by histamine using control (normoglycemic) hamsters. In these studies, FITC-labeled dextran 150,000 daltons was administered intravenously and quantified by UV-light microscopy, and the drugs used were applied topically at therapeutic concentrations. Gliclazide and glibenclamide dose-dependently decreased the macromolecular permeability increase induced by histamine. This effect of gliclazide could be blocked by nifedipine (Ca 2+ channel blocker) and not by diazoxide K + channel opener), whereas for glibenclamide it could be blocked by diazoxide and not by nifedipine. To better characterize the antioxidant capacity of gliclazide and glibenclamide, their effect on the macromolecular permeability increase induced by ischemia/reperfusion was also compared with the effect of vitamin C in diabetic hamsters (glycemia > 240 mg/dL). Total ischemia of the preparation was obtained with a cuff placed around the neck of the everted pouch. Diabetes was induced by three intraperitoneal injections of streptozotocin 50 mg/kg/d in 3 days. In diabetic hamsters during ischemia/reperfusion, gliclazide was more effective in inhibiting the macromolecular permeability increase than glibenclamide (136.0 ± 5.8 leaks/cm 2 for placebo; 68.0 ± 2.9 for 1.2 × 10 −6 mol/L gliclazide; 55.3 ± 3.5 for 1.2 × 10 −5 mol/L gliclazide; 89.2 ± 5.7 for 8 × 10 −8 mol/L glibenclamide; 107.0 ± 3.8 for 8 × 10 −7 mol/L glibenclamide; 56.7 ± 3.4 for 10 −6 mol/L vitamin C; and 20.5 ± 0.6 for 10 −5 mol/L vitamin C). Our results suggest that (1) the inhibition of the permeability increase induced by histamine elicited by gliclazide may be mediated by Ca 2+ channels, while that of glibenclamide may be mediated by K + channels, and (2) gliclazide appears to have an antioxidant capacity in ischemia/reperfusion injury similar to that of 10 −6 mol/L vitamin C. Improvement in the microcirculation was independent of the hypoglycemic properties of the drug.