A. Pedoto et al., Treatment of septic shock in rats with nitric oxide synthase inhibitors and inhaled nitric oxide, CRIT CARE M, 26(12), 1998, pp. 2021-2028
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.