Treatment of septic shock in rats with nitric oxide synthase inhibitors and inhaled nitric oxide

Objective: To evaluate the effect of treatment with a combination of nitric oxide synthase inhibitors and inhaled nitric oxide on systemic hypotension during sepsis. Design: Prospective, randomized, controlled study on anesthetized animals. Setting: A cardiopulmonary research laboratory. Subjects: Forty-seven male adult Sprague-Dawley rats. Interventions: Animals were anesthetized, mechanically ventilated with room air, and randomized into six groups: a) the control group (C, n = 6) recei ved normal saline infusion; b) the endotoxin-treated group received 100 mg/ kg iv of Escherichia coli lipopolysaccharide (LPS, n = 9); c) the third gro up received LPS, and 1 hr later the animals were treated with 100 mg/kg iv N-w-nitro-L-arginine (LNA, n = 9); d) the fourth group received LPS, and af ter 1 hr, the animals were treated with 100 mg/kg iv aminoguanidine (AG, n = 9); a) the fifth group received LPS and 1 hr later was treated with LNA p lus 1 ppm inhaled nitric oxide (LNA+NO, n = 7); f) the sixth group received LPS and 1 hr later was treated with aminoguanidine plus inhaled NO (AG+NO, n = 7). Inhaled NO was administered continuously until the end of the expe riment. Measurements and Main Results: Systemic mean blood pressure (MAP) was monit ored through a catheter in the carotid artery. Mean exhaled NO (ENO) was me asured before LPS (T-0) and every 30 mins thereafter for 5 hrs. Arterial bl ood gases and pH were measured every 30 mins for the first 2 hrs and then e very hour. No attempt was made to regulate the animal body temperature. All the rats became equally hypothermic (28.9 +/- 1.2 degrees C [SEM]) at the end of the experiment. In the control group, blood pressure and pH remained stable for the duratio n of the experiment, however, ENO increased gradually from 1.3 +/- 0.7 to 1 7.6 +/- 3.1 ppb after 5 hrs (p < .05). In the LPS treated rats, MAP decreas ed in the first 30 mins and then remained stable for 5 hrs. The decrease in MAP was associated with a gradual increase in ENO, which was significant a fter 180 mins (58.9 +/- 16.6 ppb) and reached 95.3 +/- 27.5 ppb after 5 hrs (p < .05). LNA and AG prevented the increase in ENO after LPS to the level in the control group. AG caused a partial reversal of systemic hypotension , which lasted for the duration of the experiment. LNA reversed systemic hy potension almost completely but only transiently for 1 hr, and caused sever e metabolic acidosis in all animals. The co-administration of NO with AG ha d no added benefits on MAP and pH. In contrast, NO inhalation increased the duration of the reversal in MAP after LNA, alleviated the degree of acidos is, and decreased the mortality rate (from 55% to 29%). Conclusions: In this animal model, LPS-induced hypotension was alleviated s lightly and durably after AG, but only transiently after LNA. Furthermore, co-administration of NO with AG had no added benefits but alleviated the se verity of metabolic acidosis and mortality after LNA. We conclude that nitr ic oxide synthase (NOS) inhibitors, given as a single large bolus in the ea rly phase of sepsis, can exhibit some beneficial effects. Administration of inhaled NO with NOS inhibitors provided more benefits in some conditions a nd therefore may be a useful therapeutic combination in sepsis. NO producti on in sepsis does not seem to be a primary cause of systemic hypotension. O ther factors are likely to have a major role.