Aminoethyl-isothiourea, a nitric oxide synthase inhibitor and oxygen radical scavenger, improves survival and counteracts hemodynamic deterioration in a porcine model of streptococcal shock.
OBJECTIVE
To test the effect of a continuous infusion of the nitric oxide (NO) synthase (S) inhibitor aminoethyl-isothiourea (AE-ITU) on survival time, hemodynamics, and oxygen transport in a porcine model of live group A streptococcal (GAS) sepsis. Furthermore, to examine the role of endothelin-1, histamine, and reactive oxygen species (ROS) in streptococcal shock.


METHODS
Prospective, randomized trial.


METHODS
Laboratory at a university hospital.


METHODS
Twenty-eight pigs with an average weight of 25 kg.


METHODS
Sixteen animals received a continuous infusion of live Streptococcus pyogenes 1.3 x 10(10) colony forming units/hr: eight received fluids only, and the other eight received an intravenous infusion of AE-ITU 10 mg/kg/hr starting 30 mins before the GAS challenge. Six control pigs received AE-ITU 10 mg/kg/hr iv for 5 hrs. Another six animals received half the dose of GAS over 5 hrs.


RESULTS
GAS infusion caused a rapid increase in pulmonary, hepatic, and systemic vascular resistance, followed by hypotension with a 90% lethality at 4 hrs. Treatment with AE-ITU increased 4-hr survival in septic animals from 1/8 to 8/8 and 5-hr survival from 0/8 to 5/8, prevented hypotension, and increased urine output. AE-ITU attenuated the decrease in cardiac output, liver blood flow, and oxygen delivery, and hepatic arterial blood flow as a fraction of cardiac output increased (all p < .05). Plasma nitrate/nitrite levels decreased in all animals. Inducible NOS and endothelial constitutive NOS activities in liver, gut, and lung were not increased during sepsis, nor were they decreased after AE-ITU. Plasma levels of endothelin-1 and methylhistamine increased in all septic animals and were not modified by AE-ITU. AE-ITU prevented the increase in monocyte ROS production caused by GAS. In control animals, AE-ITU caused an increase in mean arterial pressure, liver blood flow, and oxygen delivery.


CONCLUSIONS
In this model of porcine GAS-induced septic shock, which was not associated with enhanced NO production, infusion of the NOS inhibitor AE-ITU prolonged survival, prevented hypotension, and improved cardiac contractility, organ perfusion, and tissue oxygenation. These beneficial effects of AE-ITU might be a result of the combined effect of ROS scavenging and modulation of local NO production, thus improving the balance of vasodilator and vasoconstrictor forces and reducing oxidative stress.
Saetre
T
T
Research Forum, Ullevaal University Hospital, Oslo, Norway. torunn.satre@ioks.uio.no
Höiby
E A
EA
Aspelin
T
T
Lermark
G
G
Egeland
T
T
Lyberg
T
T
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D011897:Random Allocation; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality* / Q000503:physiopathology; D013290:Streptococcal Infections / Q000188:drug therapy* / Q000401:mortality* / Q000503:physiopathology; D013297:Streptococcus pyogenes; D015996:Survival Rate; D013552:Swine; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
D007550:Isothiuronium; C007687:etiron; C413842:aminoethyl-isothiourea; D009569:Nitric Oxide; D013890:Thiourea