Aminoguanidine suppresses basal macromolecular extravasation during diabetes mellitus.
The goal of this study was to determine the effect of aminoguanidine on basal macromolecular efflux from the microcirculation of the hamster cheek pouch during diabetes mellitus. We used intravital fluorescent microscopy and fluorescein isothiocyanate dextrans (FITC-dextran; mw = 70 and 20K) to examine basal macromolecular extravasation in nondiabetic hamsters, nondiabetic hamsters treated with a topical application of aminoguanidine (0.5 mM), diabetic hamsters (6-10 weeks after injection of streptozotocin), and diabetic hamsters treated with a topical application of aminoguanidine (0.5 mM). Increases in macromolecular efflux were quantitated by calculating the clearance (ml/s x 10(-6)) of FITC-dextran-70K and -20K. In nondiabetic hamsters, the clearance of FITC-dextran-70K and -20K remained relatively constant during the experimental period, although the clearance of FITC-dextran-70K was less than that for FITC-dextran-20K. Topical application of aminoguanidine did not alter basal permeability characteristics in nondiabetic hamsters. In diabetic hamsters, clearance of FITC-dextran-70K and -20K also remained relatively constant during the experimental period. However, the magnitude of clearance of FITC-dextran-70K and and -20K was significantly greater in diabetic compared to nondiabetic hamsters (P < 0.05). Topical application of aminoguanidine restored basal permeability characteristics of diabetic hamsters to that observed in nondiabetic hamsters. These findings suggest that acute treatment of the microcirculation in vivo with aminoguanidine ameliorates basal increases in extravasation of macromolecules during diabetes mellitus. We suggest that aminoguanidine suppresses basal macromolecular efflux in diabetic hamsters via inhibition of nitric oxide synthase. Thus, it appears that the use of aminoguanidine may be an important therapeutic approach for the treatment of diabetes-related vascular dysfunction.
Mayhan
W G
WG
Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska, 68198-4575, USA.
Sharpe
G M
GM
D000818:Animals; D001160:Arterioles / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose; D001835:Body Weight / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D002610:Cheek / Q000098:blood supply; D006224:Cricetinae; D003911:Dextrans / Q000493:pharmacokinetics; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008833:Microcirculation / Q000187:drug effects* / Q000378:metabolism; D008970:Molecular Weight; D011897:Random Allocation
D001786:Blood Glucose; D003911:Dextrans; D004791:Enzyme Inhibitors; D006146:Guanidines; C015219:fluorescein isothiocyanate dextran; D016650:Fluorescein-5-isothiocyanate; C004479:pimagedine