EFFECTS OF N(W)-NITRO-L-ARGININE AND DEXAMETHASONE ON EARLY EVENTS FOLLOWING LIPOPOLYSACCHARIDE INJECTION - OBSERVATIONS IN THE HAMSTER-CHEEK POUCH MICROCIRCULATION

The effects of N(W)-nitro-L-arginine (L-NAG) and dexamethasone in the microcirculatory changes observed in early stages of endotoxemia was investigated in male hamsters treated with Escherichia coli lipopolysaccharide (LPS). The cheek pouch was studied in vivo by means of intravital microscopy and mean arterial and venous pressures, mean arteriolar internal diameter, spontaneous arteriolar vasomotion, microvascular blood flow, macromolecular permeability, leukocyte adhesion, and mean survival time were evaluated in animals treated with either LPS alone or the combination of LPS with L-NAG, an inhibitor of both the constitutive and inducible NO synthases (NOs). The intravenous injection of LPS (100 mg/kg) elicited a significant reduction in mean arterial blood pressure (MABP) and arteriolar blood flow. The observed arterioles dilated and the spontaneous vasomotion ceased. The combination LPS + L-NAG, both given intravenously, prevented the reduction of MABP and the vasodilation but did not help either the reduction of arteriolar blood flow or the cessation of vasomotion. In order to separate the effect of the two NOs, a group of hamsters was pretreated with dexamethasone (10 mg/kg, also intravenously) which inhibits the induction of the inducible NO synthase (iNOs). In this group, the hypotension, vasodilation, and cessation of vasomotion were prevented but the decrease in arteriolar blood flow was not affected. The mean survival time was significantly decreased by the combination of LPS + L-NAG (35 +/- 6 h) and significantly increased by the pretreatment with dexamethasone (92 +/- 5 h) compared to LPS alone (56 +/- 7 h). Topical addition of L-NAG (1.3 ng/ml/min) did not significantly change the increased macromolecular permeability and leukocyte adhesion observed with the topical application of LPS (0.7 mug/ml/min) alone. Our results suggest that the increased NO production by the iNOs after LPS treatment could cause significant dysfunction in the microcirculation of the hamster cheek pouch. They also indicate that the use of nonselective NO synthase inhibitors could be detrimental in endotoxic shock, probably because it inhibits the iNOs which seems beneficial and the constitutive NO synthase (cNOs) which seems deleterious.