Quality of life assessment in reflux disease

It has been suggested that inhibitors of nitric oxide synthesis are of value in the treatment of hypotension during sepsis. In this pilot study, we examined the effects of inhibition of nitric oxide synthesis by continuous infusion of N(omega)-nitro-L-arginine methyl ester (L-NAME) at 1.5 mg/kg/h in a patient with severe septic shock. L-NAME produced a rise in mean arterial blood pressure and systemic vascular resistance; catecholamine infusion could be reduced. Parallel to these findings, there was a 50% reduction in cardiac output and a 5-fold rise in pulmonary vascular resistance, which resulted in severe pulmonary hypertension after 3 h of L-NAME infusion, for which the infusion had to be stopped. Following the termination of L-NAME infusion, pulmonary artery pressure and blood pressure returned to baseline values, although pulmonary and systemic vascular resistance remained elevated for several hours. We conclude that nitric oxide appears to play a role in the cardiovascular derangements during human sepsis. Inhibition of nitric oxide synthesis with L-NAME can increase blood pressure and systemic vascular resistance. However, reduced cardiac output and pulmonary hypertension are possible side effects of continuous NO synthase inhibition. These side effects necessitate careful monitoring and may hinder the clinical application of NO synthase inhibitors.     

Role of nitric oxide in sepsis-associated pulmonary edema

Transient pulmonary hypertension after inhibition of nitric oxide synthase (NOS) does not alter pulmonary reflection coefficients or lymph flows in endotoxemic sheep. To test the effects of persistent pulmonary hypertension induced by N omega-nitro-L-arginine methylester (L-NAME) and of inhaled NO on pulmonary edema, 18 sheep (three groups) were chronically instrumented with pulmonary artery catheters, femoral arterial fiberoptic thermistor catheters, and tracheostomy. The awake, spontaneously breathing animals received Salmonella typhi endotoxin (lipopolysaccharide; LPS) (10 ng/kg/ min) for 28 h. After 24 h, an airflow of 6 L/min was delivered through the tracheostomy. One group of animals (L-NAME/air) received L-NAME intravenously (25 mg/kg + 5 mg/kg/h) and breathed air. The second group (L-NAME/NO) was given L-NAME and NO (40 ppm) was added to the airflow. The third group was given NaCl 0.9% and breathed air (NaCl/air). Extravascular lung water was measured through the double-indicator dilution technique. Endotoxemia caused pulmonary edema, which was aggravated by L-NAME. Breathing of NO normalized pulmonary artery pressure (Ppa) and ameliorated pulmonary edema. Inhalation of NO may therefore be a therapeutic option for pulmonary edema associated with pulmonary hypertension.     

Nitric oxide inhalation: effects on the ovine neonatal pulmonary and systemic circulations

Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.     

The pulmonary effect of nitric oxide synthase inhibition following endotoxemia in a swine model

OBJECTIVE: To evaluate the pulmonary effect of treatment with N-nitro-L-arginine methyl ester (NAME) with and without inhaled nitric oxide (NO) in a swine model of endotoxemia. DESIGN: Randomized controlled trial. SETTING: Laboratory. INTERVENTIONS: Following a 20-minute intravenous infusion of Escherichia coli lipopolysaccharide (LPS) (200 micrograms/kg), animals were resuscitated with saline solution (1 mL/kg per minute) and observed for 3 hours while mechanically ventilated (fraction of inspired oxygen [FIO2], 0.6; tidal volume, 12 mL/kg; positive end-expiratory pressure, 5 cm H2O). Group 1 (LPS, n = 6) received no additional treatment; group 2 (NAME, n = 5) received NAME (3 mg/kg per hour) for the last 2 hours; group 3 (NO, n = 6) received NAME (3 mg/kg per hour) and inhaled NO (40 ppm) for the last 2 hours; and group 4 (control, n = 5) received only saline solution without LPS. MAIN OUTCOME MEASURES: Cardiopulmonary variables and blood gases were measured serially. The multiple inert gas elimination technique was performed at 3 hours. The wet-to-dry lung weight ratio was measured following necropsy. RESULTS: Administration of LPS resulted in pulmonary arterial hypertension, pulmonary edema, and hypoxemia with increased ventilation perfusion ratio mismatching. None of these changes were attenuated by NAME treatment alone but all were significantly improved by the simultaneous administration of inhaled NO. CONCLUSIONS: Systemic NO synthase inhibition failed to restore hypoxic pulmonary vasoconstriction following LPS administration. The deleterious effects of endotoxemia on pulmonary function can be improved by inhaled NO but not by systemic inhibition of NO synthase.     

The acute increases in vasomotor tone and blood pressure induced by carotid artery occlusion are modulated by platelet-activating factor (PAF) independently of nitric oxide release

The purpose of the present study was to investigate the involvement of nitric oxide (NO) in the modulatory role of platelet-activating factor (PAF, 1-O-hexadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine), a vasoactive phospholipid mediator synthesized by endothelial cells, on the vascular tone and arterial blood pressure. In pentobarbitone-anaesthetized rabbits, unloading of the carotid sinus baroreceptors by a bilateral carotid artery occlusion elicited a reflex rise in systemic vascular resistance, which was markedly potentiated by pretreating the animals with the PAF receptor antagonist WEB 2086 ([3-4-(2-chlorphenyl-)-9-methyl-6H-thieno-3,2-f-1,2,4-triazolo-4,3 -alpha-1,4 -diazepin-2-yl-(4-morpholinyl)-1-propanone]; 5 mg/kg, i.v.). In contrast, the inhibition of the biosynthesis of NO via NO synthase using N omega-nitro-L-arginine methyl ester (L-NAME) neither affected the systemic vasoconstriction induced by carotid artery occlusion nor modified the potentiating effect of WEB 2086. The haemodynamic alterations induced by L-NAME administration were corrected by continuous infusions of the directly-acting vasodilators sodium nitroprusside or diazoxide. The results of the present study confirm previous studies from our group suggesting the involvement of PAF in a negative feedback mechanism effective in the local regulation of vasomotor tone in anaesthetized rabbits, but exclude the participation of NO in this process.     

Pyridoxalated hemoglobin polyoxyethylene conjugate does not restore hypoxic pulmonary vasoconstriction in ovine sepsis

OBJECTIVES: Hypoxic pulmonary vasoconstriction, a protective mechanism, minimizes perfusion of underventilated lung areas to reduce ventilation-perfusion mismatching. We studied the effects of sepsis on hypoxic pulmonary vasoconstriction and attempted to determine whether hypoxic pulmonary vasoconstriction is influenced by pyridoxalated hemoglobin polyoxyethylene conjugate, a nitric oxide scavenger. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational intensive care unit at a university medical center. SUBJECTS: Nineteen female merino sheep, divided into three groups: group 1, controls (n = 5); group 2, sheep with sepsis (n = 6); and group 3, septic sheep treated with pyridoxalated hemoglobin polyoxyethylene conjugate (n = 8). INTERVENTIONS: All sheep were instrumented for chronic study. An ultrasonic flow probe was placed around the left pulmonary artery. After a 5-day recovery, a tracheostomy was performed and a double-lumen endotracheal tube was placed. Animals in groups 2 and 3 received a 48-hr infusion of live Pseudomonas aeruginosa (6 x 10(4) colony-forming units/kg/hr). After 24 hrs, sheep in group 3 received pyridoxalated hemoglobin polyoxyethylene conjugate (20 mg/kg/hr) for 16 hrs; sheep in groups 1 and 2 received only the vehicle. Hypoxic pulmonary vasoconstriction was repeatedly tested by unilateral hypoxia of the left lung with 100% nitrogen. Hypoxic pulmonary vasoconstriction was assessed as the change in left pulmonary blood flow. MEASUREMENTS AND MAIN RESULTS: In the animals in group 1, left pulmonary blood flow decreased by 62 +/- 8 (SEM)% during left lung hypoxia and remained stable during repeated hypoxic challenges throughout the study period. After 24 hrs of sepsis, left pulmonary blood flow decreased from 56 +/- 10% to 26 +/- 2% (group 2) and from 50 +/- 8% to 23 +/- 6% (group 3). In the sheep in group 2, there was no adaptation over time. Pulmonary shunt fraction increased. Pyridoxalated hemoglobin polyoxyethylene conjugate had no effect on hypoxic pulmonary vasoconstriction or pulmonary shunt. The animals receiving the bacterial infusion developed a hyperdynamic circulatory state with hypotension, decreased systemic vascular resistance, and increased cardiac output. Pyridoxalated hemoglobin polyoxyethylene conjugate increased mean arterial pressure and systemic vascular resistance but did not influence cardiac index. Pulmonary arterial pressure was increased during sepsis and increased even further after pyridoxalated hemoglobin polyoxyethylene conjugate administration. Oxygenation and oxygen delivery and uptake were not affected by pyridoxalated hemoglobin polyoxyethylene conjugate. CONCLUSIONS: Hypoxic pulmonary vasoconstriction is blunted during sepsis and there is no adaptation over time. It is not influenced by pyridoxalated hemoglobin polyoxyethylene conjugate. Pyridoxalated hemoglobin polyoxyethylene conjugate reversed hypotension and, with the exception of an increase in pulmonary arterial pressure, had no adverse effects on hemodynamics or oxygenation.     

The nitric oxide donor sodium nitroprusside protects against hepatic microcirculatory dysfunction in early endotoxaemia

OBJECTIVE: Endotoxin rapidly inhibits the activity of the constitutive endothelial nitric oxide synthase (ecNOS); this precedes the production of NO from inducible NOS (iNOS). This leaves a period in early endotoxaemia with a supposed scarcity of NO. The present study was conducted to examine the effects of external supplementation of NO on liver microcirculation and function. MATERIAL: 13 male Sprague Dawley rats. INTERVENTIONS: The rats underwent laparotomy, and the left liver lobe was exteriorised. All animals were given a bolus dose of endotoxin (LPS) 5 mg/kg intraportally. One group (n = 6) had a continuous infusion of sodium nitroprusside (SNP) 1.4 microg/kg per min started concurrently, the other group (n = 7) was treated with normal saline. The study was terminated after 3 h LPS. MEASUREMENTS AND RESULTS: Intravital microscopy was performed at baseline, at 2 h and 3 h LPS. Hepatic function was assessed by arterial ketone body ratio, acid base values, and bile flow. At baseline 1% of the sinusoids were without perfusion. After 2 h LPS this figure had risen to 9.8+/-1.5% in the SNP group versus 16.9+/-1.4% in the controls (p < 0.05 vs controls). The corresponding values after 3 h LPS were 13.5+/-1.5 versus 19.3+/-1.5% (p < 0.05 vs controls). The leukocyte count in sinusoids and venules had a similar development. Functional parameters were all slightly better preserved in the SNP group, but with no individual significance versus controls. CONCLUSIONS: Infusion of the NO donor SNP in early endotoxaemia attenuates the detrimental effects of LPS on liver microcirculation, most probably by alleviating a relative deficit of NO at the microcirculatory level.     

Differential role of endothelium-derived nitric oxide in the modulation of the systemic and pulmonary circulation in lambs

We have studied the differential role of endothelium-derived nitric oxide (EDNO) in the regulation of the systemic and pulmonary circulations of the lamb. Hemodynamic effects of NG-nitro-L-arginine methyl ester (L-NAME, 1 mg/kg i.v.), an inhibitor of NO synthesis, were determined in juvenile (6 +/- 1 weeks old) lambs, under conditions of basal and elevated vasomotor tone. Under basal conditions, L-NAME raised both systemic (SVR) and pulmonary vascular resistances (PVR) by 20-30% (increasing SVR from 0.318 +/- 0.013 to 0.385 +/- 0.015 mm Hg.min.ml-1.kg and PVR from 0.050 +/- 0.003 to 0.067 +/- 0.010 mm Hg.min.ml-1.kg). When tone was elevated in the pulmonary circulation with hypoxia (PVR was elevated by 60%, from 0.059 +/- 0.010 to 0.094 +/- 0.019 mm Hg.min.ml-1.kg), L-NAME treatment resulted in an augmented increase in PVR (PVR increased by greater than 50% to 0.140 +/- 0.024 mm Hg.min.ml-1.kg). However, when tone was elevated to a comparable degree in the systemic circulation with angiotensin infusion (SVR was elevated by 60%, from 0.432 +/- 0.065 to 0.065 to 0.634 +/- 0.113 mm Hg.min.ml-1.kg), the response to L-NAME was not augmented. Our data suggest that the role of EDNO in the modulation of the pulmonary circulation is dependent on the level of vasomotor tone, whereas its role in the systemic circulation is small and is independent of the level of vasomotor tone.     

L-NAME does not affect exercise-induced pulmonary hypertension in thoroughbred horses

The present study was carried out to examine the effects of nitric oxide synthase inhibition with Nomega-nitro-L-arginine methyl ester (L-NAME) on the right atrial as well as on the pulmonary arterial, capillary, and venous blood pressures of horses during rest and exercise performed at maximal heart rate (HRmax). Experiments were carried out on seven healthy, sound, exercise-trained Thoroughbred horses. Using catheter-tip manometers, with signals referenced at the point of the shoulder, we determined phasic and mean right atrial and pulmonary vascular pressures in two sets of experiments [control (no medications) and L-NAME (20 mg/kg iv given 10 min before exercise studies)]. The studies were carried out in random order 7 days apart. Measurements were made at rest and during treadmill exercise performed on a 5% uphill grade at 6, 8, and 14.2 m/s. Exercise on a 5% uphill grade at 14.2 m/s elicited HRmax and could not be sustained for >90 s. In quietly standing horses, L-NAME administration caused a significant rise in right atrial, as well as pulmonary arterial, capillary, and venous pressures. This indicates that nitric oxide synthase inhibition modifies the basal pulmonary vasomotor tone. In both treatments, exercise caused progressive significant increments in right atrial and pulmonary vascular pressures, but the values recorded in the L-NAME study were not different from those in the control study. The extent of exercise-induced tachycardia was significantly decreased in the L-NAME study at 6 and 8 m/s but not at 14.2 m/s. Thus, L-NAME administration may not modify the equine pulmonary vascular tone during exercise at HRmax. However, as indicated by a significant reduction in heart rate, L-NAME seems to modify the sympathoneurohumoral response to submaximal exercise.     

Study of an anti-human transthyretin immunoadsorbent. Influence of coupling chemistry on binding capacity and ligand leakage

The pig has been reported to present with a stronger hypoxic pulmonary vasoconstriction than many other species, including the dog, but it is not known whether this is associated with a different longitudinal partitioning of pulmonary vascular resistance (PVR). We investigated the relationships between cardiac output (Q) and mean pulmonary artery pressure (Ppa) minus occluded Ppa (Ppao), and effective pulmonary capillary pressure (Pc') minus Ppao, in seven minipigs and in seven dogs in hyperoxia (FI(O2) 0.4) and hypoxia (FI(O2) 0.1), first without, then with the inhalation of 80 ppm nitric oxide (NO) to inhibit any reversible component of PVR. Pc' was estimated from the Ppa decay curve following pulmonary artery balloon occlusion. In hyperoxia, minipigs compared to dogs had (Ppa - Ppao)/Q and (Pc' - Ppao)/Q plots shifted to higher pressures. Hypoxia at each level of Q increased Ppa - Ppao in minipigs more than in dogs, and Pc' - Ppao in minipigs only. Inhaled NO reversed hypoxia-induced changes in (Ppa - Ppao)/(Q and (Pc' - Ppao)/Q plots. We conclude that the minipig, compared to the dog, presents with higher PVR and reactivity including vessels downstream to the site of Pc' as determined by the arterial occlusion technique.     

Pulmonary vasoconstriction induced by mitral valve obstruction in sheep

We hypothesized that left atrial hypertension results in pulmonary vasoconstriction, which is obscured by the expected passive decrease in pulmonary vascular resistance. The objectives of this study were to demonstrate and quantify the vasoconstrictive changes that occur in the pulmonary circulation during experimental left atrial hypertension, to determine the site of vasoconstriction, and to explore its mechanism. Sheep were instrumented for measurement of pulmonary arterial (Ppa), left atrial (Pla), and systemic arterial pressures (Psa) with a Foley balloon catheter to variably obstruct the mitral valve. Distal pulmonary arterial wedge pressure (Ppaw) was determined by using a 5-Fr Swan-Ganz catheter that was advanced until it wedged with the balloon deflated. Cardiac output (CO) was estimated by thermodilution; pulmonary vascular resistances (PVR) were calculated as mean (Ppa - Pla)/CO = total PVR, (Ppa - Ppaw)/CO = upstream PVR, and (Ppaw - Pla)/CO = downstream PVR. We studied 15 awake sheep at baseline and during increases in Pla of 10 and 20 cmH2O, with and without inhalation of approximately 36 parts per million of nitric oxide. Left atrial hypertension resulted in elevation of Ppa. CO decreased only slightly at both levels of Pla elevation. Nitric oxide inhalation caused a significant decrease in PVR, which was greater as Pla increased. This vasodilator effect was most striking in downstream vessels. Experiments with phentolamine, atropine, and ibuprofen failed to reveal the mechanism of the reactive pulmonary vasoconstriction.     

Effect of nitric oxide synthesis inhibition with nebulized L-NAME on ventilation-perfusion distributions in bronchial asthma

Patients with clinically stable asthma may show ventilation-perfusion (V'A/Q') mismatch. Nitric oxide (NO), a potent endogenous vasodilator, is increased in exhaled air of asthmatics. Such an increased NO production may be detrimental for optimal V'A/Q' balance owing to the potential inhibition of hypoxic pulmonary vasoconstriction. This study was undertaken to investigate the relationship between the concentration of NO in exhaled air and the degree of gas-exchange impairment and to assess the effect of nebulized N(G)-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthesis, on gas exchange in patients with asthma. Twelve patients (four females and eight males, aged 31+/-5 yrs) with clinically stable asthma (forced expiratory volume in one second (FEV1) 80+/-5%) not treated with glucocorticoids and increased exhaled NO (58+/-9 parts per billion (ppb)) were studied. Exhaled NO, respiratory system resistance (Rrs), arterial blood gases and V'A/Q' distributions were measured before and 30, 60, 90 and 120 min after placebo or L-NAME (10(-1) M) nebulization; in eight patients pulmonary haemodynamics were also measured. At baseline no relationships between exhaled NO and gas-exchange measurements were shown. Nebulized L-NAME induced a significant decrease in exhaled NO (p< 0.001), which was maximal at 90 min (-55+/-5%). However, after L-NAME no changes in Rrs, arterial oxygen tension, the alveolar-arterial pressure difference in oxygen or V'A/Q' distributions were shown and nebulized L-NAME did not modify pulmonary artery pressure. In conclusion, the degree of gas-exchange impairment in stable asthma is not related to nitric oxide concentration in exhaled air and nitric oxide synthesis inhibition with N(G)-nitro-L-arginine methyl ester does not alter gas exchange or pulmonary haemodynamics, such that ventilation-perfusion disturbances do not appear to be related to an increased synthesis of nitric oxide in the airways.     

Effects of inhaled nitric oxide during permissive hypercapnia in acute respiratory failure in piglets

OBJECTIVE: To look for the effects of inhaled nitric oxide on oxygenation and pulmonary hemodynamics during acute hypercapnia in acute respiratory failure. DESIGN: Prospective, randomized, experimental study. SETTING: University research laboratory. SUBJECTS: Ten piglets, weighing 9 to 13 kg. INTERVENTIONS: Acute respiratory failure was induced by oleic acid infusion and repeated lung lavages with 0.9% sodium chloride. The protocol consisted of three randomly assigned periods with different PaCO2 levels. Tidal volume was reduced to induce hypercapnia. Inspiratory time was prolonged to achieve similar mean airway pressures. During permissive hypercapnia, pH was not corrected. At each PaCO2 period, the animals were ventilated with inhaled nitric oxide of 10 parts per million and without nitric oxide inhalation. MEASUREMENTS AND MAIN RESULTS: Continuous hemodynamic monitoring included right atrial, mean pulmonary arterial, and mean systemic arterial pressures, arterial and mixed venous oxygen saturations, and continuous flow recording at the pulmonary artery. In addition, airway pressures, tidal volumes, dynamic lung compliance and airway resistance, end-tidal CO2 concentrations, and arterial and mixed venous blood gases were measured. Data were obtained at baseline and after lung injury, at normocapnia, at two levels of hypercapnia with and without nitric oxide inhalation. Acute hypercapnia resulted in a significant decrease in blood pH and a significant increase in mean pulmonary arterial pressure. There was no significant change in PaO2 during normocapnia and hypercapnia. Inhaled nitric oxide significantly decreased the mean pulmonary arterial pressure during both hypercapnic periods. It significantly improved oxygenation during both normocapnia and hypercapnia. CONCLUSIONS: Acute hypercapnia resulted in a significant increase in pulmonary arterial pressure without influencing oxygenation and cardiac output. Inhaled nitric oxide significantly reduced the pulmonary hypertension induced by acute permissive hypercapnia but did not influence the flow through the pulmonary artery. Inhaled nitric oxide significantly improved oxygenation in this model of acute lung injury during normocapnia and acute hypercapnia.     

Early activation of vascular endothelium in nonobese, nondiabetic essential hypertensive patients with multiple metabolic abnormalities

OBJECTIVES: Inhibitors of nitric oxide synthesis have been suggested to be of value in the treatment of hypotension during sepsis. However, earlier clinical reports only describe the initial effects of these nitric oxide inhibitors. This study was designed to examine the effects of the prolonged inhibition of nitric oxide synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) in patients with severe septic shock. DESIGN: Prospective, nonrandomized, clinical study. SETTING: Medical-surgical intensive care unit in a university hospital. PATIENTS: Eleven consecutive patients with ongoing hyperdynamic septic shock that was unresponsive to fluid resuscitation and vasopressor therapy. INTERVENTIONS: Measurements of hemodynamic, hematologic, and biochemical variables were made before, during, and after the start of a continuous intravenous infusion of 1 mg/kg/hr of L-NAME, an inhibitor of nitric oxide synthesis, for a period of 12 hrs. MEASUREMENTS AND MAIN RESULTS: Continuous infusion of L-NAME resulted in a direct increase in mean arterial pressure from 65 +/- 3 (SEM) to 93 +/- 4 mm Hg and an increase in systemic vascular resistance from 426 +/- 54 to 700 +/- 75 dyne x sec/cm5, reaching a maximum at 0.5 hr. Pulmonary arterial pressure was increased from 31 +/- 2 to a maximum of 36 +/- 2 mm Hg at 1 hr, and pulmonary vascular resistance increased from 146 +/- 13 to a maximum of 210 +/- 23 dyne x sec/cm5 at 3 hrs. Paralleling these changes, cardiac output decreased from 10.8 +/- 0.8 to 8.7 +/- 0.7 L/min and oxygen delivery decreased from 1600 +/- 160 to 1370 +/- 130 mL/min (for all changes p < .05 as compared with the baseline value). Heart rate, cardiac filling pressures, oxygen consumption, urine production, arterial lactate concentration, and other biochemical parameters were not significantly changed by L-NAME administration (all p > .05). Arterial oxygenation was improved during L-NAME infusion, and the dosage of catecholamines could be reduced (both p< .05). Although sustained hemodynamic effects were seen, L-NAME was most effective during the early stages of administration, and the effect of L-NAME on blood pressure and vascular resistance tended to diminish throughout the continuous infusion of L-NAME. Seven of 11 patients ultimately died, with survival time ranging from 2 to 34 days. CONCLUSIONS: Nitric oxide appears to play a role in cardiovascular derangements during human sepsis. The increased blood pressure and vascular resistance values are sustained during prolonged inhibition of nitric oxide synthesis with L-NAME in patients with severe septic shock, although the hemodynamic changes are most significant in the early stages of L-NAME infusion. The high mortality rate in these patients may suggest that L-NAME has only limited effects on outcome.     

Increased nitric oxide synthesis and action preclude choroidal vasoconstriction to hyperoxia in newborn pigs

We tested the hypothesis that hyperoxia does not cause adequate constriction of choroidal vessels of the newborn (1 to 5 days old) pig, resulting in increased O2 delivery to the retina, possibly due to excess production and/or effects of vasodilators such as nitric oxide (NO). Hyperoxia (100% O2, 45 minutes) led to a decrease in retinal blood flow (RBF) of both newborn and juvenile (5 to 6 weeks old) pigs and also reduced choroidal blood flow (ChBF) in juvenile but not in newborn pigs; the absence of hyperoxia-induced ChBF response in the newborn was associated with a rise in choroidal O2 delivery. Ibuprofen (prostaglandin G/H synthase inhibitor) and 1,3-dimethyl-2-thiourea (a free radical scavenger) did not modify the choroidal hemodynamic responses to hyperoxia in newborn pigs. However, in newborn animals treated with the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME), hyperoxia caused a decrease in blood flow and O2 delivery to the choroid. Consistent with these effects of L-NAME, hyperoxia induced an increase in choroidal cGMP in newborn pigs ventilated with 100% O2 and stimulated nitrite production in isolated choroids exposed to hyperoxia from newborn but not juvenile pigs; these effects were inhibited by NOS blockers. Also, both constitutive and inducible NOS activities were higher in choroidal tissues from newborn than from juvenile animals. In addition, the vasorelaxant effect of the NO donor sodium nitroprusside in vitro was also greater on choroids from newborn than from juvenile pigs. Finally, L-NAME prevented the hyperoxia-induced increase in peroxidation products in the choroid of newborns. It is concluded that hyperoxia does not lead to a decrease in blood flow and O2 delivery to the choroid of the newborn because of increased NO synthesis and effects; since the choroid is the main source of O2 supply to the retina, the present data contribute in providing an explanation for the increased susceptibility of the immature neonate to hyperoxia-induced retinopathy.     

In pigs, inhaled nitric oxide (NO) counterbalances PAF-induced pulmonary hypertension

In 6 anesthetized mechanically ventilated pigs we have studied the effects of inhalation of 80 ppm of nitric oxide (NO) before and after platelet-activating factor (PAF) administration (50 ng/kg iv). Our results show that NO inhalation causes a decrease in pulmonary arterial pressure and in heart rate without affecting other circulatory parameters. PAF administration causes a pulmonary hypertension and a prompt and brief decrease in systemic pressure. Inhalation of NO reduces the pulmonary hypertension, without completely reversing PAF-dependent vasoconstriction. PAF administration to pigs pretreated with indomethacin produces a lesser increase in pulmonary vascular pressure. In this case, NO inhalation can restore to baseline values. Pretreatment of 3 of the 6 pigs with NG-nitro-L-arginine-methyl-ester did not prevent the prompt and brief PAF-induced systemic hypotension. In conclusion, our results show that NO reduces basal pulmonary vascular tone, acts as a pulmonary vasodilator on PAF-preconstricted vessels and is not involved in the brief systemic hypotension consequent to PAF administration.     

Right ventricular overload causes the decrease in cardiac output after nitric oxide synthesis inhibition in endotoxemia

OBJECTIVE: To determine whether the decrease in cardiac output after nitric oxide synthase inhibition in endotoxemia is due to increased left ventricular afterload or right ventricular afterload. DESIGN: Prospective, randomized, unblinded study. SETTING: Research laboratory at an academic, university medical center. SUBJECTS: Nonanesthetized, sedated, mechanically ventilated pigs. INTERVENTIONS: Pigs were infused with 250 microg/kg of endotoxin over 30 mins. Normal saline was infused to maintain pulmonary artery occlusion pressure (PAOP) at a value not exceeding 1.5 times the baseline value. Left ventricular dimensions and function were studied using echocardiography. Right ventricular volumes and ejection fraction were determined via a rapid thermistor pulmonary artery catheter. We also measured mean arterial pressure (MAP), cardiac output, pulmonary arterial pressure, and calculated pulmonary and systemic resistances. Gastric tonometry was used as an index of gastric mucosal oxygenation and peripheral oxygenation. When MAP had decreased to < or =60 mm Hg or had decreased 30 mm Hg from baseline, nine animals received NG-nitro-L-arginine methyl ester (L-NAME) at 15 mg/kg to restore MAP to baseline. A second group of animals (n = 6) continued to receive normal saline, ensuring that PAOP did not exceed 1.5 times its baseline value. A third group of pigs (n = 5) did not receive endotoxin and served as the time control. In this group, a balloon was used to occlude the descending thoracic aorta and to increase MAP by approximately the same amount as in the L-NAME group. MEASUREMENTS AND MAIN RESULTS: Endotoxin caused an increase in pulmonary arterial pressure and right ventricular volumes, and a decrease in gastric mucosal pH. Cardiac output was maintained in the animals receiving the saline infusion. By 2 hrs, pulmonary arterial pressure had decreased but was still notably higher than baseline. However, by this time, MAP had decreased to < or =60 mm Hg. L-NAME administration restored MAP to its baseline value but resulted in worsening pulmonary hypertension, increased right ventricular volumes, and decreased cardiac output, compared with the saline group. Three animals that received L-NAME died of right ventricular failure. We did not observe any evidence of left ventricular dysfunction with increased left ventricular afterload. Moreover, the restoration of MAP with L-NAME infusion did not correct gastric mucosal acidosis. No changes were noted in the time-control group. Occlusion of the thoracic aorta increased MAP but did not change cardiac output. This finding demonstrates that increases in left ventricular afterload of the magnitude seen with the infusion of L-NAME do not lead to decreases in cardiac output. CONCLUSION: The decrease in cardiac output after nitric oxide synthase inhibition in endotoxemia is due to increased right ventricular afterload and not to left ventricular afterload.     

Cerebral blood flow during hypoxemia and hemodilution in rabbits: different roles for nitric oxide?

Hypoxemia and anemia are associated with increased CBF, but the mechanisms that link the changes in PaO2 or arterial O2 content (CaO2) with CBF are unclear. These experiments were intended to examine the contribution of nitric oxide. CaO2 in pentobarbital-anesthetized rabbits was reduced to approximately 6.5 mL O2/dL by hypoxemia (PaO2 approximately 24 to 26 mm Hg) or hemodilution with hetastarch (hematocrit approximately 14% to 15%). Animals with normal CaO2 (approximately 17.5 to 18 mL O2/dL) served as controls. In part I, each animal was given 3, 10, and 30 mg/kg N omega-nitro-L-arginine methyl ester (L-NAME) intravenously (total 43 mg/kg) to inhibit production of nitric oxide. Forebrain CBF was measured with radioactive microspheres approximately 15 to 20 minutes after each dose. Baseline CBF was greater in hypoxemic rabbits (111 +/- 31 mL x 100 g-1 x min-1, mean +/- SD) than in hemodiluted (70 +/- 22 mL x 100 g-1 min-1) or control animals (39 +/- 12 mL x 100 g-1 min-1). L-NAME (which reduced brain tissue nitric oxide synthase activity by approximately 65%) reduced CBF in hypoxemic animals to 80 +/- 23 mL x 100 g-1 x min-1 (P < 0.0001), but had no significant effect on CBF in either anemic or control animals. In four additional rabbits, further hemodilution to a CaO2 of approximately 3.5 mL O2/dL increased baseline CBF to 126 +/- 21 mL x 100 g-1 min-1, but again there was no effect of L-NAME. In part II, animals were anesthetized as above, and a close cranial window was prepared. The cyclic GMP (cGMP) content of the artificial CSF superfusate was measured under baseline conditions, and then after the reduction of CaO2 to approximately 6.5 mL O2/dL by either hypoxemia or hemodilution. Concentrations of cGMP did not change during either control conditions or after hemodilution. However, cGMP increased significantly with the induction of hypoxemia. The cGMP increase in hypoxemic animals could be blocked with L-NAME. These results suggest that nitric oxide plays some role in hypoxemic vasodilation, but not during hemodilution.     

Anesthesia with sodium pentobarbital enhances lipopolysaccharide-induced cardiovascular dysfunction in rats

Lipopolysaccharide (LPS)-induced hypotension and impaired aortic contraction to norepinephrine (NE) are thought to be consequent to induction of nitric oxide synthase (iNOS). Anesthesia is often employed in studies of the mechanisms mediating LPS-induced cardiovascular dysfunction in rats. Since sympathetic nervous system activity and compensatory mechanisms can be altered by anesthesia, this study was designed to determine a) if the cardiovascular dysfunction associated with LPS (5 mg/kg, i.v.)-induced endotoxin shock is enhanced in anesthetized compared with conscious male Wistar rats, and b) the potential role of iNOS in these responses to LPS. Arterial pressure and heart rate were continuously measured via a femoral arterial cannula. Six hours after LPS, conscious rats had a stable mean arterial pressure (MAP) and were tachycardic, while anesthetized rats showed a significant decrease in MAP without tachycardia. Small mesenteric arterioles (200-300 microns) were isolated, and the endothelium was removed six h after LPS. Intraluminal diameter was continuously recorded while vessels were maintained at a constant intraluminal pressure of 40 mmHg. Norepinephrine-induced contraction and oscillations/min were impaired to a greater extent in arterioles from LPS-treated anesthetized rats than in those from conscious rats. Calcium-dependent and -independent nitric oxide formation, reflected as cGMP accumulation, were also determined in aortic rings treated with a chelator of Ca2+, EGTA, or the inhibitor of nitric oxide synthase activity, L-NAME. In rings from saline-treated conscious and anesthetized rats, cGMP accumulation was significantly reduced by EGTA and L-NAME, indicating calcium-dependent constitutive (cNOS) activity. However, in aortic rings from LPS-treated conscious and anesthetized rats, cGMP accumulation was not affected by EGTA and was significantly greater in rings from anesthetized vs. conscious rats. These results suggest that cardiovascular dysfunction is more prominent in LPS-treated anesthetized vs. conscious rats. This effect may be related to increased induction of iNOS in the presence of anesthesia.     

An autopsied case of multiple system atrophy with remarkable cerebral atrophy

OBJECTIVES: We tested the effects of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, on plasma levels of interleukin (IL) IL-6, IL-8, tumor necrosis factor-alpha (TNFalpha) and nitrite/nitrate (NO2-/ NO3-) in patients with severe septic shock. DESIGN: Prospective clinical study. SETTING: Surgical intensive care unit at a university hospital. PATIENTS: 11 consecutive patients with severe septic shock. INTERVENTIONS: Standard hemodynamic measurements were made and blood samples taken at intervals before, during, and after a 12-h infusion of L-NAME 1 mg x kg(-1) x h(-1) for determination of plasma IL-6, IL-8, TNFalpha and NO2-/NO3- concentration. MEASUREMENTS AND RESULTS: Patients with sepsis had increased plasma levels of IL-6, IL-8, TNFalpha and NO2-/NO3- (p < 0.05). Plasma levels of IL-6. IL-8, and NO2-/NO- were negatively correlated with systemic vascular resistance (r = -0.62, r = -0.65, and r = -0.78, respectively, all p < 0.05). Continuous infusion of L-NAME increased mean arterial pressure and systemic vascular resistance, with a concomitant reduction in cardiac output (all p < 0.01). No significant changes were seen in levels of plasma IL-6, IL-8, and NO-/NO3- during the 24-h observation period. Plasma levels of TNFalpha were significantly reduced during L-NAME infusion compared to baseline (p < 0.05). CONCLUSIONS: NO plays a role in the cardiovascular derangements of human septic shock. Inhibition of NO synthesis with L-NAME does not promote excessive cytokine release in patients with severe sepsis.