Xw. Qu et al., Roles of nitric oxide synthases in platelet-activating factor-induced intestinal necrosis in rats, CRIT CARE M, 27(2), 1999, pp. 356-364
Objective: To examine the role of constitutive and inducible nitric oxide s
ynthases (cNOS and iNOS) in platelet-activating factor (PAF) induced shock
and intestinal injury.
Design: Prospective, randomized, controlled experimental study.
Setting: Hospital research laboratory.
Subjects: Young adult male Sprague-Dawley rats were anesthetized and studie
d.
Interventions: Rats were injected with PAF, either alone or after the follo
wing pretreatments: a) selective iNOS inhibitors aminoguanidine or S-methyl
isothiourea; b) 3 morpholinosydnonimine, a NO donor; c) S-methylisothiourea
c 3-morpholinosydnonimine; and d) antineutrophil antibody (to deplete neut
rophils), Measurements and Main Results: Blood pressure, hematocrit, white
blood cell counts, intestinal injury, and intestinal cNOS and iNOS activiti
es were assessed. We found that: a) cNOS is the predominant NOS in the inte
stine and its activity is inversely correlated to the level of tissue injur
y; b) there is a time-dependent increase in cNOS activity in sham-operated
animals, which was abolished by PAF; c) Western blotting and immunohistoche
mistry showed iNOS present in the normal intestine, localizing mainly in cr
ypt cells; d) iNOS inhibitors attenuated PAF induced injury in animals with
high cNOS activity, but had no protective effect in animals with low cNOS
activity; e) 3-morpholinosydnonimine, alone or together with S-methylisothi
ourea, alleviated PAF induced injury; and f) neutrophil depletion blocked t
he suppressive effect of PAF on cNOS and prevented injury.
Conclusions: We conclude that cNOS and iNOS play different roles in PAF-ind
uced intestinal injury, Caution should be exerted concerning potential ther
apeutic uses of iNOS inhibitors.