nitroarginine and Shock--Septic

The pharmacokinetics of N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, was investigated in patients with septic shock.. Blood was sampled at intervals before, during and after 12-h infusion of L-NAME 1 mg x kg(-1) x h(-1) in nine septic shock patients for determination of plasma concentrations by high-performance liquid chromatography (HPLC). In three patients the renal clearance of the drug was determined.. Incubation of L-NAME with plasma and blood in vitro revealed hydrolysis to N(G)-nitro-L-arginine (L-NOARG), the active inhibitor of NO synthesis. L-NOARG did not undergo further degradation. Continuous intravenous infusion of 1 mg x kg(-1) x h(-1) of L-NAME for 12 h in patients with septic shock increased blood pressure and resulted in increasing plasma concentrations of L-NOARG (Cmax 6.2 microg x ml(-1) at 12 h) whereas L-NAME concentrations reached a plateau within 1.5 h (Cmax 1.0 microg x ml(-1)). After the infusion was stopped L-NAME disappeared from the plasma rapidly (half-life 19.2 min) whereas L-NOARG concentration declined slowly (half-life 22.9 h). The calculated volume of distribution for L-NAME was 0.451 x kg(-1) body weight and 1.961 x kg(-1) for L-NOARG. The renal clearance for L-NOARG was 3.5% of total body clearance for L-NOARG, whereas L-NAME could not be detected in urine.. We conclude that vasoconstriction with L-NAME in septic patients may result from hydrolysis to L-NOARG, the active inhibitor of NO synthesis. The long plasma half-life and large volume of distribution for L-NOARG suggests extensive distribution to extravascular tissues. Since renal excretion is minimal, elimination of the metabolite L-NOARG follows other pathways.

Topics: Chromatography, High Pressure Liquid; Humans; Hydrolysis; In Vitro Techniques; Injections, Intravenous; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroarginine; Shock, Septic

Sepsis and its complications, hypotension, shock, and multiorgan failure continue to represent a significant cause of mortality among hospitalized patients, affecting approximately 200,000 patients per year in the US and 100,000 in Europe (Dal Nogare, A.R. 1991. Am. J. Med. Sci. 302:50-65.). Incidence rates appear to be increasing, probably due to an increase in the population with risk factors such as diabetes or invasive procedures. Activation of cytokines by endotoxins and subsequent formation of nitric oxide is of central pathogeneic importance in sepsis. In this study we show that polymerized bovine hemoglobin (Biopure 2) restores both cardiovascular and renal functions in an endotoxin-induced shock model in rats. These effects are compared to those of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine, and hydroxyethyl starch, the latter currently in clinical use for intravenous volume replacement. Our results clearly indicate that polymerized hemoglobin but not nitric oxide synthase inhibition or volume replacement normalize cardiovascular and kidney function in acute septic shock. This new therapeutic approach is readily applicable to controlled clinical trials because polymerized hemoglobin has been tested in humans and is therefore available for such studies.

Topics: Animals; Blood Pressure; Cardiovascular Physiological Phenomena; Cattle; Enzyme Inhibitors; Glomerular Filtration Rate; Heart Rate; Hematocrit; Hemoglobins; Hydroxyethyl Starch Derivatives; Kidney; Lipopolysaccharides; Male; Nitric Oxide; Nitroarginine; Plasma Substitutes; Polymers; Rats; Renal Circulation; Shock, Septic

Fluid loading is an essential part of cardiovascular resuscitation in septic shock. We hypothesized that fluid administration increases blood flow velocity and thus endothelial shear stress, causing the release of nitric oxide by the vascular endothelium. Because of endothelial dysfunction in sepsis, this mechanism would be less effective in septic animals. Fluid loading may have different effects in septic compared with control animals.. Prospective, randomized, controlled study.. Animal research laboratory.. Male Sprague-Dawley rats.. We tested the involvement of nitric oxide in the fluid-induced cardiovascular response after administration of lipopolysaccharide (5 mg/kg, n = 10) or vehicle (control, n = 10) in rats subsequently randomized after 165 mins to receive L-N(G)-nitroarginine (7.5 mg/kg) or saline (n = 5 in each group). At 180 mins, all animals received hydroxyethyl starch (fluid loading, 15 mL/kg in 15 mins). Reversal of L-N(G)-nitroarginine was studied with an intravenous bolus of L-arginine (300 mg/kg).. Lipopolysaccharide injection induced a hypokinetic shock (low blood pressure: -30% +/- 9%, p < .05), low cardiac output (aortic pulsed-Doppler probe: -20% +/- 8, p < .05), and unchanged systemic conductance, which turned into a hyperkinetic shock by fluid loading. Pretreatment with L-N(G)-nitroarginine totally abolished this fluid loading-induced vasodilation in control rats but only partially in lipopolysaccharide-treated rats, suggesting an altered endothelial response after lipopolysaccharide injection. Maximal aortic blood flow acceleration was used as an index of left ventricular systolic function. The improvement of maximal aortic blood flow acceleration observed during fluid loading in lipopolysaccharide-treated or control animals was blunted by L-N(G)-nitroarginine pretreatment, suggesting the involvement of nitric oxide in the myocardial response to fluid loading.. These results suggest that the endothelium participates in the hemodynamic response to fluid loading in control rats, but less in rats with septic shock, secondary to an altered nitric oxide-dependent vasodilation.

Topics: Animals; Aorta; Blood Flow Velocity; Cardiac Output, Low; Disease Models, Animal; Endothelium, Vascular; Enzyme Inhibitors; Escherichia coli; Injections, Intravenous; Lipopolysaccharides; Male; Nitric Oxide; Nitroarginine; Prospective Studies; Random Allocation; Rats; Rats, Sprague-Dawley; Resuscitation; Shock, Septic; Vasodilation

(HCl x N(G)-NO2-Arg)2Lys-OCH3, (HCl x N(G)-NO2-Arg)2Lys-OH, [(HCl x N(G)-NO2-Arg)2Lys]2Lys-OCH3, and [(HCl x N(G)-NO2-Arg)2Lys]2Lys-OH were synthesized by use of a solution method. Their effect on septic shock was studied in vivo. The results indicate that increasing the number of N(G)-NO2-Arg residues in a molecule may be useful to improve the response to septic shock.

Topics: Animals; Blood Pressure; Enzyme Inhibitors; Nitroarginine; Random Allocation; Rats; Rats, Wistar; Shock, Septic

To evaluate the effect of treatment with a combination of nitric oxide synthase inhibitors and inhaled nitric oxide on systemic hypotension during sepsis.. Prospective, randomized, controlled study on anesthetized animals.. A cardiopulmonary research laboratory.. Forty-seven male adult Sprague-Dawley rats.. Animals were anesthetized, mechanically ventilated with room air, and randomized into six groups: a) the control group (C, n=6) received normal saline infusion; b) the endotoxin-treated group received 100 mg/kg i.v. of Escherichia coli lipopolysaccharide (LPS, n=9); c) the third group received LPS, and 1 hr later the animals were treated with 100 mg/kg i.v. Nw-nitro-L-arginine (LNA, n=9); d) the fourth group received LPS, and after 1 hr, the animals were treated with 100 mg/kg i.v. aminoguanidine (AG, n=9); e) the fifth group received LPS and 1 hr later was treated with LNA plus 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 experiment.. Systemic mean blood pressure (MAP) was monitored through a catheter in the carotid artery. Mean exhaled NO (ENO) was measured before LPS (T0) and every 30 mins thereafter for 5 hrs. Arterial blood gases and pH were measured every 30 mins for the first 2 hrs and then every 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 duration of the experiment, however, ENO increased gradually from 1.3+/-0.7 to 17.6+/-3.1 ppb after 5 hrs (p< .05). In the LPS treated rats, MAP decreased 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 after 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 hypotension almost completely but only transiently for 1 hr, and caused severe metabolic acidosis in all animals. The co-administration of NO with AG had 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 acidosis, and decreased the mortality rate (from 55% to 29%).. In this animal model, LPS-induced hypotension was alleviated slightly and durably after AG, but only transiently after LNA. Furthermore, co-administration of NO with AG had no added benefits but alleviated the severity of metabolic acidosis and mortality after LNA. We conclude that nitric oxide synthase (NOS) inhibitors, given as a single large bolus in the early phase of sepsis, can exhibit some beneficial effects. Administration of inhaled NO with NOS inhibitors provided more benefits in some conditions and therefore may be a useful therapeutic combination in sepsis. NO production in sepsis does not seem to be a primary cause of systemic hypotension. Other factors are likely to have a major role.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Escherichia coli Infections; Free Radical Scavengers; Guanidines; Hemodynamics; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Random Allocation; Rats; Rats, Sprague-Dawley; Shock, Septic; Time Factors

Calcium ion (Ca++)-independent nitric oxide (NO) synthase activity in animals was markedly induced by treatment with endotoxin, but NO levels in various tissues removed from endotoxin-treated animals have not been reported. The role of NO during an endotoxin-induced septic shock remains controversial.. ICR mice, randomly divided into one of six treatment groups, received intraperitoneal injections as follows: phosphate-buffered saline; Escherichia coli LPS (LPS); N(omega)-nitro-L-arginine (L-NNA); N(omega)-nitro-D-arginine (D-NNA); LPS plus L-NNA; and LPS plus D-NNA. The mice were either monitored for mortality or killed for nitrite/nitrate assays and histologic analysis.. NO levels in many tissues were markedly increased by injection of LPS, and administration of L-NNA increased mortality rates of LPS-treated mice, in association with an increase in tissue damage in the lung, liver, and kidney.. The endogenous NO generated during LPS-mediated septic shock could be protective.

Topics: Animals; Arginine; Enzyme Inhibitors; Escherichia coli; Kidney; Lipopolysaccharides; Liver; Lung; Mice; Mice, Inbred ICR; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Random Allocation; Shock, Septic; Survival Rate

Decreased contractility of myocytes after cytokine exposure can be prevented by nitric oxide synthase inhibition. Whether this is true in an intact animal model of sepsis is unknown. Anesthetized pigs were pretreated with saline or a nitric oxide synthase inhibitor, N omega-nitro-L-arginine, and then treated with saline or endotoxin. We measured hemodynamics and left ventricular pressures (Millar catheter) and volumes (conductance catheter). Left ventricular contractility was assessed using the slope (E(max)) of the end-systolic pressure-volume relationship. Four hours after endotoxin infusion, E(max) had decreased by 44 +/- 5% (P < 0.05) and mean arterial pressure had decreased by 30 +/- 10% (P < 0.05). Pretreatment with N omega-nitro-L-arginine significantly reduced the decrease in E(max) to 28 +/- 3% (P < 0.05) and prevented the decrease in mean arterial pressure. However, it also raised pulmonary arterial pressure. We conclude that nitric oxide contributes to the early decrease in left ventricular contractility after endotoxin in the intact animal. However, the vascular effects of nitric oxide synthase inhibition increase right and left ventricular afterloads, which were detrimental to cardiac function.

Topics: Animals; Arginine; Blood Pressure; Cardiac Output; Endotoxins; Enzyme Inhibitors; Hemodynamics; Myocardial Contraction; Nitric Oxide Synthase; Nitroarginine; Pulmonary Artery; Shock, Septic; Sodium Chloride; Swine; Ventricular Function, Left

Enhanced production of nitric oxide has been implicated in cardiac and vascular dysfunction associated with septic and endotoxic shock. To test this hypothesis, conscious rats were administered endotoxin. 6 h later, the rats were anesthetized, arterial pressure was measured, and hearts were removed for Langendorff perfusion in the absence and presence of .01 microM isoproterenol. Left ventricular developed pressure was 61 +/- 6 mmHg in control rats 39 +/- 5 mmHg in endotoxin-treated rats. Inotropic responses to isoproterenol were unaffected by endotoxin treatment. Administration of nitric oxide synthase (NOS) inhibitors (NG-nitro-L-arginine and aminoguanidine) prior to endotoxin did not improve left ventricular function in endotoxin-treated rats. Dexamethasone pretreatment, however, prevented endotoxin-induced cardiac depression. These results suggest that cardiac depression during endotoxemia is not caused by NOS activation and increased nitric oxide production. Furthermore, the cardioprotectant actions of dexamethasone are not related to its ability to inhibit inducible NOS expression.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Cardiac Output, Low; Dexamethasone; Guanidines; Heart Rate; Hemodynamics; Hypotension; Isoproterenol; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley; Shock, Septic

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Blood Pressure; Cardiac Output; Endotoxins; Nitric Oxide Synthase; Nitroarginine; Rabbits; Shock, Septic

To elucidate the role of nitric oxide (NO) in septic shock, we measured hemodynamic and pulmonary gas changes in anesthetized dogs after intravenous administration of bacterial lipopolysaccharide (LPS) with or without NO synthase inhibitor, NG-nitro-L-arginine (L-NNA). Infusion of LPS (250 ng.kg-1.min-1) for 2 h decreased mean arterial pressure over 1-4 h. Although L-NNA (10 mg/kg) blocked LPS-induced hypotension, it decreased cardiac index, oxygen delivery index, arterial pH, and arterial PO2 and increased systemic vascular resistance index in the presence or absence of LPS. Administration of NG-nitro-D-arginine (D-NNA, 10 mg/kg) alone caused fewer hemodynamic effects (increased systemic vascular resistance index and decreased cardiac index) than L-NNA alone. Our study provides evidence that L-NNA prevents endotoxin-induced hypotension but decreases cardiac output and oxygen delivery, effects that may, in part, be due to a nonspecific NO synthase-independent event. Thus clinical use of NO synthase inhibitors for the treatment of septic shock should be cautiously considered.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Biological Availability; Dogs; Hemodynamics; Lipopolysaccharides; Nitric Oxide Synthase; Nitroarginine; Oxygen; Pulmonary Gas Exchange; Shock, Septic

To evaluate the possible effects of a combination of systemic nitric oxide synthesis inhibition (to increase mean arterial blood pressure) and nitric oxide inhalation (to decrease pulmonary vascular pressure) in porcine endotoxin shock.. Prospective trial.. Laboratory at a large university medical center.. Ten pathogen-free pigs weighing 19 to 25 kg.. After surgical preparation, all pigs received a continuous infusion of Escherichia coli lipopolysaccharide endotoxin (15 micrograms/kg/hr) for 2 hrs. After 1 hr of endotoxemia, nitric oxide inhalation (50 parts per million) and NG-nitro-L-arginine infusion (50 mg/kg/hr) were initiated in six pigs. Four pigs served as controls and received only a lipopolysaccharide infusion.. NG-nitro-L-arginine infusion and nitric oxide inhalation prevented the further decrease in mean arterial blood pressure seen in the control pigs (p < .05), but did not restore mean arterial blood pressure back to basal values. Cardiac output decreased significantly compared with controls during NG-nitro-L-arginine infusion/nitric oxide inhalation (p < .01). Systemic vascular resistance, which was below basal values in the controls after 2 hrs of endotoxemia, was markedly increased by NG-nitro-L-arginine/nitric oxide, to higher values than those observed in the basal state (p < .01). In the control pigs, mean pulmonary arterial pressure and pulmonary vascular resistance showed a biphasic increase. In the NG-nitro-L-arginine/nitric oxide treated group, the second phase increase in mean pulmonary arterial pressure did not occur (p < .01). However, there was no difference in pulmonary vascular resistance between the groups. Renal vascular resistance was unchanged in controls, while NG-nitro-L-arginine/nitric oxide induced a four-fold increase in renal vascular resistance (p < .001). There was no statistical difference in urine production between the groups. PaO2 values were higher and PaCO2 tensions were lower in the treated pigs than in the controls. Arterial pH and base excess did not differ. Arterial plasma epinephrine, norepinephrine, and neuropeptide Y concentrations increased during the lipopolysaccharide infusion in both groups, with a tendency toward higher concentrations in the pigs receiving NG-nitro-L-arginine/nitric oxide. Arterial plasma endothelin-1-like immunoreactivity in these pigs was significantly higher at the end of the treatment than in the controls.. In this model of porcine endotoxin shock, the combination of NG-nitro-L-arginine infusion and nitric oxide inhalation attenuated pulmonary hypertension and improved gas exchange; it also prevented development of further systemic hypotension, but impaired cardiac output and increased systemic and renal vascular resistances to supranormal levels. NG-nitro-L-arginine/nitric oxide did not reduce sympathetic nervous system activation or metabolic acidosis.

Topics: Administration, Inhalation; Animals; Arginine; Drug Evaluation, Preclinical; Drug Therapy, Combination; Endothelins; Escherichia coli Infections; Female; Infusions, Intravenous; Male; Neuropeptide Y; Nitric Oxide; Nitroarginine; Shock, Septic; Specific Pathogen-Free Organisms; Swine

The sensitivity of animals to endotoxin differs significantly between species. Thus, factors that determine the susceptibility to endotoxin may play important roles in the pathogenesis of septic shock. In order to determine the mechanism responsible for susceptibility to endotoxin, the effect of lipopolysaccharide (LPS) on the circulatory status of Propionibacterium acnes (PA)-sensitized rats was studied. Following the intravenous administration of a low dose of LPS, the arterial blood pressure of PA-treated rats, but not of normal animals, progressively decreased; the PA-sensitized animals died of circulatory shock within 7 h of LPS administration. N omega-nitro-L-arginine (NA) reduced the depressor effect of LPS by an L-arginine-inhibitable mechanism. Administration of LPS markedly increased the level of the inducible type of nitric oxide (NO) synthase in various tissues, including the aorta, of PA-treated rats but not of control animals. LPS also increased plasma levels of nitrate plus nitrite and aortic levels of cGMP. Dexamethasone inhibited the de novo synthesis of NO synthase in the aorta and other tissues and reduced the depressor effect of LPS. These and other findings suggest that induction of nitric oxide synthase in resistant arteries might underlie the pathogenesis of LPS-induced hypotension in PA-sensitized animals and the mechanism responsible for the susceptibility to endotoxin.

Topics: Amino Acid Oxidoreductases; Animals; Aorta; Arginine; Blood Pressure; Cyclic GMP; Dexamethasone; Enzyme Induction; Heart Rate; Hepatectomy; Hypersensitivity; Lipopolysaccharides; Male; Nitrates; Nitric Oxide Synthase; Nitrites; Nitroarginine; Propionibacterium acnes; Rats; Rats, Wistar; Shock, Septic; Splenectomy; Survival Analysis; Tissue Distribution

The effects of NW-nitro-L-arginine (L-NAG) and dexamethasone in the microcirculatory changes observed in early stages of endotoxemia was investigated in male hamsters treated with Escherichia coli lipopolysaccharide (LPS). The cheek pouch was studied in vivo by means of intravital microscopy and mean arterial and venous pressures, mean arteriolar internal diameter, spontaneous arteriolar vasomotion, microvascular blood flow, macromolecular permeability, leukocyte adhesion, and mean survival time were evaluated in animals treated with either LPS alone or the combination of LPS with L-NAG, an inhibitor of both the constitutive and inducible NO synthases (NOs). The intravenous injection of LPS (100 mg/kg) elicited a significant reduction in mean arterial blood pressure (MABP) and arteriolar blood flow. The observed arterioles dilated and the spontaneous vasomotion ceased. The combination LPS + L-NAG, both given intravenously, prevented the reduction of MABP and the vasodilation but did not help either the reduction of arteriolar blood flow or the cessation of vasomotion. In order to separate the effect of the two NOs, a group of hamsters was pretreated with dexamethasone (10 mg/kg, also intravenously) which inhibits the induction of the inducible NO synthase (iNOs). In this group, the hypotension, vasodilation, and cessation of vasomotion were prevented but the decrease in arteriolar blood flow was not affected. The mean survival time was significantly decreased by the combination of LPS + L-NAG (35 +/- 6 h) and significantly increased by the pretreatment with dexamethasone (92 +/- 5 h) compared to LPS alone (56 +/- 7 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arginine; Capillary Permeability; Cell Adhesion; Cheek; Cricetinae; Dexamethasone; Escherichia coli Infections; Hemodynamics; Injections, Intravenous; Lipopolysaccharides; Male; Microcirculation; Microscopy, Video; Nitroarginine; Shock, Septic

The role of nitric oxide (NO) inhibition on liver circulation during sepsis is unknown. To answer this question, we studied the effects of L-arginine (the substrate for the NO synthase), linsidomine (a direct NO donor), and N omega-nitro-L-arginine (an NO inhibitor) on the liver circulation in anesthetized rabbits previously injected with endotoxin (Escherichia coli, Salmonella enteridis, and Salmonella minnesota, 400 micrograms each). After endotoxin administration, and without fluid resuscitation, rabbits showed a hypodynamic shock with decrease in mean arterial pressure (MAP) and aortic blood flow velocity. Portal vein blood flow velocity decreased, whereas hepatic artery blood flow velocity increased. Saline or treatments were injected, 75 min after endotoxin administration. In saline-treated rabbits, MAP, aortic and portal vein blood flow velocities remained steady but hepatic artery blood flow velocity decreased. Only N omega-nitro-L-arginine (7.5 mg/kg, intravenously) significantly increased MAP compared to saline treatment. However, aortic, portal vein, and hepatic artery blood flow velocities were lower in rabbits treated with N omega-nitro-L-arginine than in saline-treated rabbits. L-Arginine (600 mg/kg, intravenously) increased aortic blood flow and portal vein blood flow velocity with no change on hepatic artery blood flow velocity. In contrast, linsidomine (1 mg) increased both hepatic flows. These results show that NO inhibition after endotoxin injection reduces systemic and liver flows, while NO release from linsidomine improves them. These findings question the usefulness of NO inhibition during septic shock, particularly as hepatic failure frequently occurs in the evolution of the disease.

Topics: Animals; Arginine; Blood Flow Velocity; Blood Pressure; Hepatic Artery; Liver Circulation; Male; Mesenteric Arteries; Molsidomine; Nitric Oxide; Nitroarginine; Portal Vein; Rabbits; Shock, Septic; Vasodilator Agents

Septic shock is characterized by systemic vasodilation and an impaired reactivity to vasoconstrictor agents. It has been suggested that an excessive release of nitric oxide has a role in this hemodynamic derangement.. To investigate whether inhibition of nitric oxide synthesis by the administration of N omega-nitro-L-arginine (LNNA), improves the vasoconstrictor effects of catecholamines in sepsis.. Mechanically ventilated and pentobarbital-anesthetized sheep received either no treatment (n = 6) or LNNA (100 mg/kg IV bolus, n = 4). Other sheep (septic group) received live Escherichia coli (E coli) (1,5* 10(9) micro-organisms/kg over 30 min) followed 1 hour later by either no treatment (n = 5) or LNNA (100 mg/kg IV bolus, n = 7). After those interventions, all sheep were given noradrenaline in a continuous IV infusion at three different doses (0.5, 1.5, and 4.5 micrograms, kg-1, min-1). Cardiovascular parameters were recorded at maximal blood pressure response achieved with each dose.. The administration of live E coli to the septic group resulted in systemic hypotension, high cardiac output, and hyperlactatemia. The LNNA caused a significant systemic and pulmonary vasoconstriction in both septic and nonseptic sheep. In nonseptic sheep, noradrenaline induced a significant increase in systemic vascular resistance (from 2,973 +/- 637 to 4,561 +/- 1,287 dyn/s/cm-5/m-2), whereas the increase caused in those that received LNNA was nonsignificant (5,562 +/- 3,489 to 6,693 +/- 2,871 dyn, s, cm-5, m-2). Septic sheep showed a nonsignificant vasoconstriction during the infusion of noradrenaline (from 1,438 +/- 1,132 to 2,244 +/- 1,391 dyn/s/cm-5/m-2). However, treatment with LNNA markedly improved the vasoconstrictor effect of noradrenaline (from 2,804 +/- 2,317 to 4,894 +/- 3,435 dyn/s/cm-5/m-2). The dose-response curve of systemic vascular resistance in these LNNA-pretreated septic sheep became very similar to the corresponding curve obtained in nonseptic animals.. Inhibition of nitric oxide synthesis by the administration of LNNA significantly improves the vasoconstrictor effect of noradrenaline in septic sheep, allowing an increase in systemic vasomotor tone similar to that observed in nonseptic sheep. It is concluded that increased synthesis of nitric oxide contributes to the depressed vascular reactivity to vasoconstrictor agents characteristic of sepsis.

Topics: Animals; Arginine; Dose-Response Relationship, Drug; Escherichia coli Infections; Nitric Oxide; Nitroarginine; Norepinephrine; Sheep; Shock, Septic; Vascular Resistance; Vasoconstriction

To verify the effect of nitric oxide system modification during sepsis, not only in terms of pressure but also in terms of perfusion flow.. Experimental, comparative study.. Laboratory of a university hospital.. Twenty-six New Zealand male rabbits (2 to 2.5 kg body weight) were studied under anesthesia.. Nitric oxide pathways were modified during shock-induced hypotension, using L-arginine (600 mg/kg) and L-nitro-arginine (7.5 mg/kg), which were infused 75 mins after endotoxin injection.. Mean arterial pressure (MAP) and cardiac output, as well as ascending aortic velocity, were measured and aortic conductance (aortic velocity/MAP in cm/sec/mm Hg) was calculated. Both L-arginine and L-nitro-arginine increased MAP to the pre-endotoxin level, but only L-arginine increased aortic velocity in association with a marked increase in aortic conductance (p < .001). L-nitro-arginine significantly (p < .05) decreased aortic velocity as compared with the control endotoxin group, with an intense vasoconstriction as shown by a significant (p < .001) decrease in aortic conductance.. These results, along with the high mortality rate in the L-nitro-arginine treated group, challenge the hypothesis that nitric oxide release inhibition has a beneficial effect in septic shock.

Topics: Animals; Arginine; Blood Pressure; Cardiac Output; Endotoxins; Male; Nitric Oxide; Nitroarginine; Rabbits; Shock, Septic

When NG-nitro-L-arginine, a nitric oxide synthase inhibitor, administration was started 5 min prior to shock induction in anesthetized dogs, a partial restoration was observed in endotoxin-induced shock and a complete recovery in platelet activating factor (PAF)-induced shock. When NG-nitro-L-arginine infusion was started 5 min after shock induction, no significant recovery was observed in endotoxin-induced shock and a complete recovery in PAF-induced shock. These data indicate that enhanced production of nitric oxide by vascular endothelial cells may contribute to endotoxin- or PAF-induced shock and also that some mediators including inducible nitric oxide synthase and/or cellular damage might be involved in endotoxin-induced shock.

Topics: Amino Acid Oxidoreductases; Analysis of Variance; Animals; Arginine; Dogs; Endothelium, Vascular; Endotoxins; Female; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Platelet Activating Factor; Shock; Shock, Septic

Role of endothelium-derived relaxing factor on vascular reactivity in endotoxin-induced shock. Chinese J. Physiol. The present study showed that E. coli lipopolysaccharide (LPS; 5 mg/kg, i.v.) produced a maximal and significant reduction in mean arterial blood pressure in the anesthetized rat. Pretreatment with N omega-nitro-L-arginine (50 mg/kg, i.v.) produced an increase in mean arterial blood pressure and completely abolished the LPS-induced hypotension. In vitro, it was designed to analyse the mechanisms underlying the LPS-induced hypotension by using various contractile and relaxant agents. Phenylephrine and high-K(+)-induced contraction was less in mesenteric arterial rings from LPS-treated rats than in rings from control rats. The removal of endothelium significantly enhanced the contraction induced by phenylephrine and high-K+ in LPS-treated rats, whereas in control rats, only the contraction induced by phenylephrine was enhanced. In contrast, the relaxation elicited by acetylcholine, A23187, L-arginine and nitroglycerin was greater in mesenteric arterial rings from LPS-treated rats than those from control rats. However, the greater relaxation induced by acetylcholine in LPS-treated rats was completely abolished by N omega-nitro-L-arginine or methylene blue. Additionally, the acetylcholine-induced relaxation was absent by removal of the endothelium. These results suggest that LPS treatment induces the production of nitric oxide from vascular endothelial cells and/or smooth muscle cells then impair the contractile response to vasoconstrictors and enhance the relaxation to vasodilators in small mesenteric arteries.

Topics: Animals; Arginine; Blood Pressure; Blood Vessels; Endothelium, Vascular; In Vitro Techniques; Lipopolysaccharides; Male; Mesenteric Arteries; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide; Nitroarginine; Rats; Rats, Sprague-Dawley; Shock, Septic; Vasoconstrictor Agents; Vasodilator Agents

Topics: Arginine; Hemodynamics; Humans; Nitric Oxide; Nitroarginine; Shock, Septic

Although various mediators such as platelet activating factor, anaphylatoxin and cytokines are considered to be involved in the pathology of endotoxin-induced shock, an endothelium-derived relaxing factor (EDRF), nitric oxide (NO) or its related substance, has recently been shown as a vasodilating factor that is produced from L-arginine. On the other hand, NG-nitro-L-arginine (L-NNA) is shown to inhibit NO production from L-arginine. Thus, in order to examine a possible involvement of NO in the shock, the effect of L-NNA administration was studied on the hemodynamics and plasma hormone levels during endotoxin-induced shock in anesthetized dogs. Twenty-five mongrel dogs were divided into the following 5 groups; (1) In group C, only physiological saline was administered. (2) In group L, a bolus injection of L-NNA (4 mg/kg B.W.) was followed by a continuous infusion of the agent (0.05 mg/kg B.W./min) for 120 min. (3) In group E, lipopolysaccharide (LPS) E. Coli 011:B4 2.625 mg/kg body weight was administered. (4) In group LE, L-NNA administration (bolus and continuous) the same as in group L was started 5 min before the injection of LPS. (5) In group EL, L-NNA administration (bolus and continuous) was started 5 min after the injection of LPS. In Group LE, MAP decreased to -45.9 mmHg 5 min after LPS injection and -33.0 mmHg 120 min from pre-level. The levels of MAP from 15 to 90 min were significantly higher than those in Group E. In Group EL, MAP decreased to -61.4 mmHg 5 min after LPS injection and this low level (-59.5 mmHg) continued for 120 min. A protecting effect of L-NNA against LPS-induced hypotension was clearly observed only when administration of the agent was started before LPS injection. These results indicated that LPS induced shock could be produced by a possible increase of NO production in the vascular endothelial cells. The other finding in the present experiment using anesthetized animals was that L-NNA had a stimulatory action on some endocrine systems such as the renin-aldosterone system and pituitary-adrenal axis, although the exact mechanism of this action of L-NNA on such systems was unclear.

Topics: Adrenocorticotropic Hormone; Aldosterone; Animals; Arginine; Blood Pressure; Cardiac Output; Dogs; Female; Heart Rate; Hemodynamics; Hormones; Hydrocortisone; Male; Nitric Oxide; Nitroarginine; Renin; Shock, Septic

Nitric oxide (10 ppm) inhaled by pigs before or during endotoxin shock induced by an infusion of E. coli lipopolysaccharide. Nitric oxide inhalation selectively attenuated pulmonary hypertension during endotoxin infusion without influencing mean arterial blood pressure and cardiac output. Upon cessation of nitric oxide inhalation, pulmonary artery pressure rapidly increased to levels seen in endotoxin-treated controls. The oxygenation and pH of arterial blood were significantly higher in the animals receiving nitric oxide. A marked increase in arterial plasma noradrenaline and neuropeptide Y was seen in endotoxin-treated control pigs while in the nitric oxide-treated pigs this increase was markedly reduced. The increase in arterial plasma endothelin-1 was not influenced by nitric oxide inhalation. Infusion of L-arginine (substrate for nitric oxide synthesis) also attenuated the pulmonary hypertension but was not selective for the pulmonary vasculature. L-Nitro-arginine (a nitric oxide synthesis inhibitor) initiated a rapid but brief elevation of arterial blood pressure and of pulmonary artery pressure as well as a reduction in cardiac output. Nitric oxide inhalation selectively reduces pulmonary hypertension in porcine endotoxin shock and improves arterial oxygenation and pH with a marked attenuation of sympathetic activation.

Topics: Administration, Inhalation; Animals; Arginine; Blood Gas Analysis; Blood Pressure; Endothelins; Female; Hemodynamics; Hypertension, Pulmonary; Male; Neuropeptide Y; Nitric Oxide; Nitroarginine; Norepinephrine; Pulmonary Circulation; Pulmonary Gas Exchange; Shock, Septic; Swine; Vascular Resistance

To study the role of nitric oxide in the hemodynamic changes of sepsis.. Prospective, randomized, controlled, intervention study.. Twenty-five sheep randomized to four groups: Group A (n = 8, nonseptic sheep) received NG-nitro L-arginine (20 mg/kg i.v.) followed 15 mins later by L-arginine (200 mg/kg i.v.); group B (n = 4, nonseptic sheep) received L-arginine followed 15 mins later by NG-nitro L-arginine; group C (n = 7, septic sheep) received NG-nitro L-arginine (20 mg/kg i.v.) alone; group D (n = 6, septic sheep) received L-arginine (200 mg/kg i.v.) followed by NG-nitro L-arginine (20 mg/kg i.v.).. Sheep were anesthetized with pentobarbital, mechanically ventilated and monitored with a pulmonary artery catheter, a peripheral artery catheter, and a Miller catheter in the left ventricle. Sepsis was induced by the intravenous administration of live Escherichia coli (1.5 x 10(9) microorganisms/kg over 30 mins), which resulted in systemic hypotension, pulmonary hypertension, high cardiac output, and hyperlactatemia. Acetylcholine was administered before and after each intervention.. In nonseptic sheep (groups A and B) NG-nitro L-arginine induced an increase in mean blood pressure (BP), pulmonary arterial pressure, and systemic and pulmonary vascular resistances, accompanied by a decrease in cardiac index and the first derivative of left ventricular pressure. L-arginine administered to normal sheep induced systemic vasodilation. In the sepsis groups (groups C and D), the increases in BP and systemic vascular resistances induced by NG-nitro L-arginine were significant but less marked than in nonseptic sheep. Pretreatment of septic sheep with L-arginine totally abolished the NG-nitro L-arginine induced increases in systemic and pulmonary vascular resistances in this group. The administration of L-arginine in these animals induced both systemic and pulmonary vasodilation. Acetylcholine-mediated vasodilation was severely impaired in sepsis. In this condition, pretreatment with L-arginine improved the response to acetylcholine.. These data support the view that nitric oxide plays a significant role in modulating systemic and pulmonary vasomotor tone in normal and septic sheep. L-arginine produced systemic vasodilation in normal sheep, whereas both systemic and pulmonary vasodilation were observed in septic animals. The impaired response to an endothelium-dependent vasodilator in sepsis was improved by the previous administration of L-arginine.

Topics: Acetylcholine; Animals; Arginine; Disease Models, Animal; Drug Evaluation, Preclinical; Escherichia coli Infections; Hemodynamics; Infusions, Intravenous; Injections, Intravenous; Nitric Oxide; Nitroarginine; Random Allocation; Sheep; Shock, Septic