We have previously shown that administration of
glucosamine after
trauma-
hemorrhage (TH) improved cardiac output and organ perfusion, and this was associated with increased levels of O-linked
N-acetylglucosamine (O-GlcNAc) on
proteins in the heart and brain. An alternative means of increasing O-GlcNAc levels is by inhibition of O-linked N-
acetylglucosaminidase, which catalyzes the removal of
N-acetylglucosamine from
proteins, with O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate (
PUGNAc). The goal of this study, therefore, was to determine whether
PUGNAc administration after TH also improves recovery of organ perfusion and function. Fasted male rats were bled to and maintained at a mean arterial blood pressure of 40 mmHg for 90 min, followed by fluid
resuscitation.
Intravenous administration of
PUGNAc (200 micromol/kg
body weight) 30 min after the onset of
resuscitation significantly improved cardiac output compared with the vehicle controls (12.3 +/- 1.3 mL/min per 100 g
body weight vs. 25.5 +/- 2.0 mL/min per 100 g
body weight; P < 0.05), decreased total peripheral resistance (6.6 +/- 0.8 mmHg/mL per minute per 100 g
body weight vs. 3.7 +/- 0.3 mmHg/mL per minute per 100 g
body weight; P < 0.05), and increased perfusion of critical organ systems, including the kidney and liver, determined at 2 h after the end of
resuscitation. Treatment with
PUGNAc also attenuated the TH-induced increase in plasma
IL-6 levels (864 +/- 112 pg/mL vs. 392 +/- 188 pg/mL; P < 0.05) and
TNF-alpha levels (216 +/- 21 pg/mL vs. 94 +/- 11 pg/mL; P < 0.05) and significantly increased O-GlcNAc levels in the heart, liver, and kidney. Thus,
PUGNAc, like
glucosamine, improves cardiac function and organ perfusion and reduced the level of circulating
IL-6 and
TNF-alpha after TH. The similar effects of
glucosamine and
PUGNAc support the notion that the protection associated with both interventions is mediated via increased
protein O-GlcNAc levels.