L-arginine does not reverse impaired agonist-induced increases in macromolecular efflux during diabetes mellitus

Objective: The first goal of this study was to determine the effect of diabetes mellitus on agonist induced increases in venular macromolecular permeability of the hamster cheek pouch. The second goal was examine the role for an alteration in the availability of L-arginine to nitric oxide synthase in impaired agonist-induced increases in macromolecular permeability during diabetes. Methods: We used intravital fluorescent microscopy and fluorescein isothiocyanate dextran (FITC-dextran; mw = 70 K) to examine macromolecular extravasation from post-capillary venules in non-diabetic and diabetic (2 weeks after injection of streptozotocin) hamsters in response to histamine and substance P. Increases in extravasation of macromolecules were quantitated by counting the number of venular leaky sites and by calculating the clearance (ml/s x 10^-6) of FITC-dextran-70K. Results: In non-diabetic hamsters, histamine (1.0 and 5.0 μM) and substance P (50 and 100 nM) increased permeability of the cheek pouch microcirculation to FITC-dextran- 70K. In contrast, histamine- and substance P-induced increases in macromolecular extravasation were markedly reduced in diabetic hamsters. Next, we investigated whether alterations in histamine- and substance P- induced changes in macromolecular extravasation in diabetic hamsters may be related to an alteration in the availability of L-arginine. We examined whether exogenous application of L-arginine (100 μM) could restore impaired histamine- and substance-P-induced increases in macromolecular extravasation in diabetic hamsters. We found that L-arginine potentiated agonist-induced increases in macromolecular extravasation in non-diabetic hamsters, but did not alter responses in diabetic hamsters. Conclusion: These findings suggest that short-term diabetes mellitus alters agonist-induced alterations in microvascular permeability. The mechanism of altered microvascular permeability during diabetes mellitus does not appear to be related to an impaired availability of L-arginine.