thiourea and Shock--Septic

Topics: Animals; Arginine; Disease Models, Animal; Enzyme Induction; Enzyme Inhibitors; Guanidines; Humans; Nitric Oxide Synthase; omega-N-Methylarginine; Rats; Shock, Septic; Thiourea

Increased production of nitric oxide (NO) and prostaglandins contribute to development of hypotension during endotoxemia. We have previously demonstrated that endotoxemia-induced increase in NO production suppresses renal cytochrome P450 (CYP) 4A expression and activity, and that selective inhibition of inducible NO synthase (iNOS) with 1,3-PBIT restores renal CYP 4A protein and activity and mean arterial pressure (MAP). By using cyclooxygenase (COX) inhibitor indomethacin, we investigated herein whether prostaglandins, via NO production, inhibit renal CYP 4A1 protein expression and CYP 4A activity and contribute to the endotoxin-induced hypotension. In conscious male Sprague-Dawley rats, endotoxin (10 mg/kg, intraperitoneal (i.p.)) reduced MAP, increased serum nitrite and bicyclo PGE2 levels, renal nitrite production and iNOS protein expression, and decreased renal CYP 4A1 protein expression and CYP 4A activity after 4 h injection. All of the endotoxin-induced changes, except for increase in renal nitrite production, were prevented by indomethacin (5 mg/kg, i.p. 1 h after endotoxin). The effects of indomethacin on the endotoxin-induced decrease in MAP, CYP 4A1 protein expression and CYP 4A activity were minimized by the CYP 4A inhibitor, aminobenzotriazole (50 mg/kg, i.p. 1 h after endotoxin). These data suggest that prostaglandins produced during endotoxemia increase iNOS protein expression and NO synthesis, and decrease CYP 4A protein expression and CYP 4A activity and that inhibition of iNOS or COX restores renal CYP 4A protein level and CYP 4A activity and MAP presumably due to increased production of arachidonic acid metabolites derived from CYP 4A.

Topics: Amitrole; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Blotting, Western; Cytochrome P-450 CYP4A; Dinoprostone; Endotoxins; Enzyme Inhibitors; Hypotension; Indomethacin; Kidney; Male; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prostaglandins; Rats; Rats, Sprague-Dawley; Shock, Septic; Thiourea

1. Our study was undertaken to investigate whether bacterial endotoxin/lipopolysaccharide (LPS) affects the neurogenic vasopressor response in rats in vivo by presynaptic mechanisms and, if so, to characterize the type of presynaptic receptor(s) operating in the initial phase of septic shock. 2. In pithed and vagotomized rats treated with pancuronium, electrical stimulation (ES) (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerve fibers or intravenous bolus injection of noradrenaline (NA) (1-3 nmol x kg(-1)) increased the diastolic blood pressure (DBP) by about 30 mmHg. Administration of LPS (0.4 and 4 mg x kg(-1)) under continuous infusion of vasopressin inhibited the neurogenic vasopressor response by 25 and 50%, respectively. LPS did not affect the increase in DBP induced by exogenous NA. 3. The LPS-induced inhibition of the neurogenic vasopressor response was counteracted by the cannabinoid CB(1) receptor antagonist SR 141716A (0.1 micromol x kg(-1)), but not by the CB(2) receptor antagonist SR 144528 (3 micromol x kg(-1)), the vanilloid VR1 receptor antagonist capsazepine (1 micromol x kg(-1)) or the histamine H(3) receptor antagonist clobenpropit (0.1 micromol x kg(-1)). The four antagonists by themselves did not affect the increase in DBP induced by ES or by injection of NA in rats not exposed to LPS. 4. We conclude that in the initial phase of septic shock, the activation of presynaptic CB(1) receptors by endogenously formed cannabinoids contributes to the inhibition of the neurogenic vasopressor response.

Topics: Animals; Autonomic Fibers, Postganglionic; Autonomic Fibers, Preganglionic; Blood Pressure; Camphanes; Capsaicin; Decerebrate State; Disease Models, Animal; Electric Stimulation; Germany; Imidazoles; Infusions, Intravenous; Lipopolysaccharides; Male; Norepinephrine; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Presynaptic; Rimonabant; Shock, Septic; Solvents; Thiourea; Vagotomy; Vasomotor System; Vasopressins

Topics: Animals; Enzyme Inhibitors; Gram-Positive Bacterial Infections; Humans; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Shock, Septic; Thiourea

To elucidate the possible roles of nitric oxide (NO), endothelin-1 (ET-1), and reactive oxygen species (ROS) in the pathophysiology of serogroup A streptococcal (GAS) peritoneal sepsis, we investigated the effects of aminoethylisothiourea (AE-ITU), an inducible NO synthase (iNOS) inhibitor, and a ROS scavenger, and the ET-1 receptor antagonist bosentan. In rats, live GAS inocula, 3 x 10(8) and 1 x 10(9) cfu/kg, entailed a 24-h mortality of 10% and 90%, respectively. GAS caused increases in tissue iNOS activity (9 h), in serum nitrite/nitrate (9-24 h), and in intracellular leukocyte ROS levels (3-6 h). These changes were all prevented by the pre-treatment with AE-ITU. A novel finding was that AE-ITU also prevented the GAS-induced marked increase in plasma ET-1 at 6 h. Short-term (7-h) survival was improved by both AE-ITU and by bosentan. The mechanism(s) for the beneficial effects of AE-ITU may possibly be a combined mode of action; iNOS inhibition, ROS scavenging, and inhibition of the increase in plasma ET-1 caused by GAS.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Shock, Septic; Streptococcal Infections; Streptococcus pyogenes; Sulfonamides; Survival Rate; Thiourea; Time Factors

The effects of endotoxemia on the cardiac function and contractility, oxygen radical production by polymorphonuclear leukocytes (PMNL-CL), cardiac antioxidant reserve (LV-CL), antioxidant enzymes (superoxide dismutase [SOD], catalase, glutathione peroxidase [GSH-P(X)]) and malondialdehyde (MDA); and plasma creatine kinase (CK) and lactate in the absence or presence of dimethylthiourea (DMTU), an antioxidant, in anesthetized dogs were studied. Dogs were assigned to three groups: group 1, control; group II, endotoxin (ET) (5 mg/kg body wt intravenously), and group III, ET + DMTU (500 mg/kg intravenously). ET produced decreases in the cardiac function and contractility, antioxidant reserve, antioxidant enzymes; and increases in PMNL-CL, cardiac MDA, plasma CK, and lactate. Pretreatment with DMTU attenuated the ET-induced cardiac dysfunction and changes in the cardiac MDA, antioxidant reserve, and antioxidant enzymes, PMNL-CL, and plasma CK and lactate levels. These results suggest that reactive oxygen species may be involved in the deterioration of cardiac function and contractility, and cellular injury during endotoxic shock and that antioxidants may be of value in the treatment of endotoxic shock.

Topics: Animals; Blood Pressure; Dogs; Female; Free Radical Scavengers; Heart Rate; Male; Myocardial Contraction; Reactive Oxygen Species; Shock, Septic; Superoxide Dismutase; Thiourea; Vascular Resistance; Ventricular Function, Left

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.. Prospective, randomized trial.. Laboratory at a university hospital.. Twenty-eight pigs with an average weight of 25 kg.. 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.. 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.. 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.

Topics: Animals; Disease Models, Animal; Female; Hemodynamics; Isothiuronium; Male; Nitric Oxide; Random Allocation; Shock, Septic; Streptococcal Infections; Streptococcus pyogenes; Survival Rate; Swine; Thiourea

Previous studies have shown an increased mortality in response to endotoxin in 24-hr-old neonatal rats compared with older neonates and adults. This increased susceptibility may be related to increased nitric oxide (NO) and thromboxane (TxB2) production. Twenty-four-hour-old neonatal rat pups were given either N(G)-nitro-L-arginine methyl ester (L-NAME; a nonspecific NO synthase inhibitor), S-methylthioisourea (SMT; a specific NO synthase inhibitor), or molsidomine (a NO donor) subcutaneously prior to or after an LD50 of intracardiac endotoxin. Mortality was followed for 72 hr. There was no statistically significant difference in mortality between control animals and those pretreated with L-NAME, SMT, or molsidomine. A trend toward increased mortality with nonspecific NO synthase inhibition and decreased mortality with the NO donor was noted. Splenic cells were obtained for in vitro cytokine stimulation studies. In vitro adherent splenic cell stimulation studies confirmed an increase in NO production with NO donor pretreatment and decreased production of NO with NO synthase inhibition pretreatment. There was no difference in TxB2 production with either the NO synthase inhibitor or the NO donor. In conclusion, at the several doses employed, neither nonselective or selective NO synthase inhibitors nor NO donors prevented endotoxin-induced mortality in rat neonatal shock. Although these findings do not preclude possible involvement of NO in neonatal pathophysiology, increased NO production thus does not appear to be the primary determinant of the increased susceptibility of the neonatal rat to endotoxic shock.

Topics: Animals; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Female; Molsidomine; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Shock, Septic; Spleen; Thiourea

A rat model of endotoxic shock was used to evaluate the effects of dimethylthiourea, a putative hydroxyl radical scavenger, in the alterations of lung phosphatidylcholine biosynthesis found during endotoxemia. Treatment of rats with dimethylthiourea, just before lipopolysaccharide injection, resulted in a decreased lipid peroxidation and an increase in phosphatidylcholine biosynthesis, although it did not prevent the body weight loss or the increase in lung weight and lung protein content associated with the lung injury induced by lipopolysaccharide. Our results suggest that phosphatidylcholine biosynthesis is impaired by processes in which hydroxyl radicals are implicated, although other oxygen free radical species, not removed by dimethylthiourea, can be also involved in lipopolysaccharide mediated lung injury.

Topics: Animals; Body Weight; Hydroxyl Radical; Lipid Peroxidation; Lipopolysaccharides; Lung; Male; Organ Size; Phosphatidylcholines; Rats; Rats, Wistar; Shock, Septic; Superoxide Dismutase; Thiourea