Effective inhibition of nitric oxide production by aminoguanidine does not reverse hypotension in endotoxaemic rats.
BACKGROUND
Excess production of nitric oxide (NO) by the inducible NO synthase (iNOS) has been implicated in the pathophysiology of septic shock. Using methaemoglobin (metHb) and the stable NO metabolite nitrate as markers of NO formation, we assessed the effect of iNOS blockade by aminoguanidine (AG) on hypotension and NO formation in endotoxaemic rats.


METHODS
In 32 male Wistar rats under chloralose anaesthesia, MetHb (at 15 and 330 min, respectively) and plasma nitrate (at 330 min) were determined. Mean arterial pressure, heart rate and haematocrit were monitored. The LPS group (n=8) received bacterial endotoxin (LPS), 3 mg kg(-1) i.v. and was subsequently monitored for 5 h. At 2 h after LPS, the LPS+AG20 group (n=8) received AG, 5 mg kg(-1), and 5 mg kg(-1) h(-1) for the remaining 3 h. The LPS+AG100 group (n=8) instead received 25 mg kg(-1), followed by 25 mg kg(-1) h(-1). The NaCl group (n=8) was given corresponding volumes of isotonic saline.


RESULTS
AG decreased the LPS-induced rise in plasma nitrate by about 50% in the LPS+AG20 group. MetHb levels, however, were not appreciably reduced by this dose. Both NO metabolites reached control levels after the higher dose of AG. LPS caused a progressive decrease in haematocrit. AG did not influence the LPS-induced hypotension, tachycardia or haemodilution.


CONCLUSIONS
AG inhibited NO formation in a dose-dependent way. Yet, AG had no haemodynamic effects, suggesting a minor cardiovascular influence of iNOS in this endotoxin model, in parallel to what has been found in microbial sepsis.
Metcalf
K
K
Department of Anaesthesiology and Intensive Care and Clinical Research Centre, University Hospital, Linköping, Sweden. Kerstin.Metcalf@lio.se
Jungersten
L
L
Lisander
B
B
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000150:complications / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology*; D007022:Hypotension / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar
D006146:Guanidines; D009566:Nitrates; D009569:Nitric Oxide; D008706:Methemoglobin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine