L-ARGININE DOES NOT REVERSE IMPAIRED AGONIST-INDUCED INCREASES IN MACROMOLECULAR EFFLUX DURING DIABETES-MELLITUS

The first goal of this study was to determine the effect of diabetes m ellitus on agonist-induced increases in venular macromolecular permeab ility of the hamster cheek pouch. The second goal was examine the role for an alteration in the availability of L-arginine to nitric oxide s ynthase in impaired agonist-induced increases in macromolecular permea bility during diabetes. Methods: We used intravital fluorescent micros copy 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 extra vasation of macromolecules were quantitated by counting the number of venular leaky sites and by calculating the clearance (ml/s x 10(-6)) o f FITC-dextran-70K. Results: In non-diabetic hamsters, histamine (1.0 and 5.0 mu M) and substance P (50 and 100 nM) increased permeability o f the cheek pouch microcirculation to FITC-dextran-70K. In contrast, h istamine- and substance P-induced increases in macromolecular extravas ation were markedly reduced in diabetic hamsters. Next, we investigate d whether alterations in histamine- and substance P-induced changes in macromolecular extravasation in diabetic hamsters may be related to a n alteration in the availability of L-arginine. We examined whether ex ogenous application of L-arginine (100 mu M) could restore impaired hi stamine- and substance-P-induced increases in macromolecular extravasa tion in diabetic hamsters. We found that L-arginine potentiated agonis t-induced increases in macromolecular extravasation in non-diabetic ha msters, but did not alter responses in diabetic hamsters. Conclusion: These findings suggest that short-term diabetes mellitus alters agonis t-induced alterations in microvascular permeability. The mechanism of altered microvascular permeability during diabetes mellitus does not a ppear to be related to an impaired availability of L-arginine.