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PubMed1984

Cardiovascular improvement due to RA642, a pyrimido-pyrimidine derivative, in canine endotoxin shock.

The cardiovascular effects of a pyrimido-pyrimidine derivative, RA642, were studied during endotoxin shock in pentobarbital-anesthetized dogs. In the control group, 30 min after intravenous administration of Escherichia coli endotoxin (1 mg/kg) mean blood pressure (MBP) and cardiac output (CO) fell significantly from 125 +/- 8 mmHg (mean +/- SE) to 65 +/- 8 mmHg and from 1.57 +/- 0.17 liter/min to 0.84 +/- 0.13 liter/min, respectively. Left ventricular (LV)dP/dtmax, renal blood flow (RBF), heart rate (HR), and central venous pressure (CVP) were also reduced significantly after endotoxin administration. Following the injection of vehicle 30 min after the endotoxin, all cardiovascular parameters in the control group remained decreased. A rapid significant rise in portal venous pressure (PoP) occurred and was maintained until the end of the experiment. Endotoxin caused an initial transient rise of total peripheral resistance (TPR) followed by a prolonged decrease. In the treated group, RA642 (0.25 mg/kg, IV), injected 30 min after the endotoxin, produced significant increases in MBP (from 62 +/- 6 mmHg to 93 +/- 7 mmHg), CO (from 0.92 +/- 0.111 liter/min to 1.28 +/- 0.18 liter/min), LVdP/dtmax (from 1600 +/- 100 mmHg/sec to 2100 +/- 300 mmHg/sec), and RBF (from 46 +/- 10 ml/min to 61 +/- 11 ml/min) within 15 min. There was a gradual return toward the pretreatment levels in each parameter 30 min after the endotoxin. The values of each parameter in the treated group were maintained significantly higher than those in the control group until the end of the experiment (90 min after the treatment). RA642 caused a rapid return of the reduced HR and the elevated PoP to the preendotoxin level. CVP recovered somewhat, though insignificantly, toward the preendotoxic value by the treatment. Following treatment, TPR was maintained at the pretreatment level. The results of this study provide evidence that RA642 exerts beneficial cardiovascular actions in endotoxin shock, restoring blood flow to vital organs without jeopardizing normal perfusion pressure and without increasing heart rate.

Animals↗
PubMed1983

The role of vasopressin in the maintenance of cardiovascular function during early endotoxin shock.

This study was conducted as an initial step to elucidate the role of vasopressin in the events leading to irreversible shock. The influence of vasopressin on the maintenance of cardiovascular and respiratory function during early endotoxin shock was evaluated. Conscious, unrestrained male Sprague-Dawley rats (SD) and male homozygous Brattleboro rats (B) lacking vasopressin were anesthetized with 2% enflurane and cannulas were placed in the carotid artery and jugular vein. After recovery from anesthesia, endotoxin (20 mg/kg) was administered. Endotoxin in the B caused an immediate drop in blood pressure to below 40 mm Hg with no recovery. This resulted in death for all ten animals within 3 1/2 hours; eight of ten had expired within 90 min. In contrast, the blood pressure response of the SD dropped to 70 mm Hg but recovered to values near control until sacrificed 240 min after endotoxin. Corticosteroid treatment (300 mg/kg) administered 30 min before endotoxin in the B prevented the severe decrease in blood pressure with values falling to and remaining near 70 mm Hg for the 240-min observation period. All treated animals survived this period. Heart rates in the SD increased sharply after endotoxin and continued to rise, whereas both treated and untreated B increased slowly. Respiration rates for the untreated B were severely depressed until death after endotoxin, whereas the SD and treated B remained at or above control. The results implicate vasopressin in the maintenance of cardiovascular function during the early phase of shock induced by endotoxin, and demonstrate the ability of corticosteroid to substantially improve cardiovascular integrity in the absence of vasopressin.

Adrenal Cortex Hormones↗
PubMed1981

The effect of leucine on plasma insulin following endotoxin shock in the rat.

We have previously documented the ability of exogenous L-leucine to accelerate the endotoxin shock syndrome. In this report we have tested the hypothesis that the mechanism for this action of leucine was via an induction of pancreatic insulin hypersecretion. Pentobarbital-anesthetized rats were injected with 1 mg/100 gm S. enteritidis endotoxin (LD90) or vehicle and infused with either Krebs Henseleit vehicle or 0.153 M leucine to a dose of 7.6 mmole/kg. Following leucine administration, plasma concentrations of leucine decayed at an exponential rate in both endotoxin-treated and sham-treated groups. The extrapolated initial leucine concentration in the endotoxin-treated rats was significantly higher than the sham rats, indicating a lower circulating blood volume in the endotoxin-treated group. In the vehicle and endotoxin-treated group, insulin levels exhibited a biphasic response, significantly lower at 30 minutes and significantly higher at three hours. In the leucine- and endotoxin-treated groups, insulin levels were markedly higher 0.5, 2, and 3 hours after leucine infusion. In the two non-endotoxin treated groups, no significant changes in insulin levels were noted after infusion. Therefore, the shock accelerating action of leucine may be due to a direct stimulation of insulin secretion inducing a prolonged hyperinsulinemia.

Animals↗
PubMed1963

Mechanisms of endotoxin tolerance. I. Relationship between tolerance and reticuloendothelial system phagocytic activity in the rabbit.

Pyrogenic tolerance following 7 daily intravenous injections of 2.0 microg/kg E. coli endotoxin in albino rabbits was associated with significant increases in RES phagocytic activity as measured with colloidal carbon. Nevertheless, 4 hours after RES blockade with thorotrast (3 ml/kg), the tolerant rabbits exhibited significantly lower fever indices following intravenous endotoxin challenge than did non-tolerant control animals despite comparably depressed capacities to clear carbon from the blood. Moreover, plasma from rabbits tolerant to endotoxin induced significant tolerance in normal rabbits prepared by thorotrast blockade without enhancing the depressed carbon clearance. This passive protection extended to heterologous endotoxins. Analysis of the data indicates that RES blockade does not abolish tolerance; rather blockade resets the reactivity to endotoxin in the normal and tolerant animal, rendering both exquisitely reactive, but permitting retention of the major portion of tolerance. Apparently the tolerant animal possesses a dual endotoxin defense system. One system is abolished by thorotrast; the other is in part humoral, accounts for the greater portion of tolerance, and is thorotrast-resistant. The nature of the humoral component is not defined but is consistent with that of an opsonin with high endotoxin specificity.

Animals↗
PubMed2004

Endotoxin has an indirect vasodilatory effect on isolated human skeletal muscle arterioles.

BACKGROUND: Septic shock and its effects are a major cause of mortality in the intensive care environment. The exact effect and mechanism of endotoxin has yet to be fully described. With a better understanding of this process, better clinical tools could be developed to treat these patients. HYPOTHESIS: Endotoxin has no direct effect on human skeletal muscle microvasculature and requires the release of an endothelial-derived factor to produce the vasodilation seen in gram-negative sepsis. DESIGN: Benchtop research using an isolated arteriole model with controlled exposure to endotoxin. SETTING: University medical center. METHODS: First-order arterioles (approximately 150- micro m diameter) were isolated from human cremasteric muscles and pressurized to physiologic levels before exposure to an endotoxin-rich effluent with and without an upstream conduit vessel (superficial epigastric vein). The vasodilatory effect was measured with videomicroscopy and compared with control samples. MAIN OUTCOME MEASURES: Mean vessel diameter and percentage of loss in tone. RESULTS: When compared with controls, the isolated arteriole had no significant response when exposed to endotoxin alone (3.5% change in basal tone). When the endotoxin was allowed to pass over an upstream conduit vessel, the arteriole showed marked dilation (14.2% loss of basal tone). CONCLUSIONS: This study demonstrates that endotoxin has no direct vasodilatory effect on human skeletal muscle arterioles, but it is the release of an endothelial factor from the upstream conduit vessels that produces the loss of tone in the microvasculature. Further research is ongoing to characterize the factors involved (nuclear factor-kappaB, tumor necrosis factor alpha, and interleuklin 6) for possible clinical intervention (antioxidants, cyclosporine, and nitric oxdide synthase inhibitors).

Arterioles↗
PubMed1987

Endotoxin promotes the translocation of bacteria from the gut.

Experiments were performed in mice to determine whether endotoxin could cause bacteria normally colonizing the gut to spread systemically, a process termed bacterial translocation. Endotoxin given intraperitoneally promoted bacterial translocation in a dose-dependent fashion from the gut to the mesenteric lymph node (MLN). The incidence of bacterial translocation to the MLN was similar whether the endotoxin was administered intramuscularly or intraperitoneally, although the number of bacteria colonizing the MLN was greater with intraperitoneal endotoxin. The incidence and magnitude of endotoxin-induced bacterial translocation were similar between CD-1 and C3H/HeJ (endotoxin-resistant) mice, indicating that bacterial translocation is not prevented by genetic resistance to endotoxin. Thus, it appears that the gut may serve as a reservoir for bacteria causing systemic infections during endotoxemia.

Animals↗
PubMed1988

Endotoxin causes hydrogen peroxide-induced lung lipid peroxidation and prostanoid production.

We studied the role of hydrogen peroxide release on endotoxin-induced lung injury in unanesthetized sheep with chronic lung lymph fistulas. We also further defined the relationship between endotoxin injury, lipid peroxidation, and prostaglandin production. Sheep were given endotoxin alone (1 microgram/kg) or pretreated with catalase (32,500 U/kg) or ibuprofen (12.5 mg/kg). Endotoxin alone resulted in an early prostanoid release, lipid peroxidation measured as circulating conjugated dienes both one and four hours after the administration of endotoxin, pulmonary hypertension, hypoxia, and increased protein permeability. Permeability was monitored by lymph flow and lymph protein content. Catalase pretreatment significantly attenuated all of these aspects of the endotoxin response. Ibuprofen prevented the early lung changes and blocked prostanoid release but did not attenuate the increased permeability. In addition, cyclo-oxygenase inhibition had a dual effect on lipid peroxidation, increasing initial conjugated diene levels while suppressing the later release. The initial effect was clearly related to cyclo-oxygenase blockade. The early conjugated diene release appears to be related to arachidonic acid metabolism and does not correspond to the degree of increased permeability. We conclude that H2O2 plays a major role in lung injury after endotoxin.

Animals↗
PubMed1988

A single dose of endotoxin increases intestinal permeability in healthy humans.

To investigate the effects of endotoxin on gut barrier function, we performed paired studies of intestinal permeability in healthy humans (N = 12) receiving intravenous Escherichia coli endotoxin (4 ng/kg) or 0.9% saline solution. Two nonmetabolizable sugars, lactulose and mannitol, which are standard permeability markers, were administered orally, 30 minutes before and 120 minutes after the test injection. The 12-hour urinary excretion of these substances after endotoxin/saline solution administration was used to quantitate intestinal permeability. After endotoxin administration systemic absorption and excretion of lactulose increased almost two-fold (mean +/- SEM, 263 +/- 36 mumol per 12 hours vs 145 +/- 19 mumol per 12 hours during saline studies). Similar but less marked alterations in mannitol absorption and excretion occurred after endotoxin injection (5.7 +/- 0.3 mmol per 12 hours vs 4.9 +/- 0.3 mmol per 12 hours). When individual 12-hour lactulose excretion after endotoxin administration was related to the magnitude of systemic responses, a significant relationship occurred between lactulose excretion and elaboration of norepinephrine and between lactulose excretion and minimum white blood cell count. These data suggest that a brief exposure to circulating endotoxin increases the permeability of the normal gut. These observations are consistent with the hypothesis that during critical illness, prolonged or repeated exposure to systemic endotoxins or associated cytokines may significantly compromise the integrity of the gastrointestinal mucosal barrier.

Administration, Oral↗
PubMed1996

Impact of different classes antimicrobial agents on plasma endotoxin activity.

OBJECTIVE: To investigate the influence of different classes and doses of antibiotics on endotoxin release in gram-negative infection in a rat model of intra- abdominal infection. DESIGN: Immediately after intraperitoneal inoculation of Escherichia coli (5 x 10(7) colony-forming units/kg), anesthetized Wistar rats were treated with a single intravenous dose of an antimicrobial agent: cefotaxime (40 mg/kg), ciprofloxacin (3 mg/kg or 6 mg/kg), imipenem (7 mg/kg or 14 mg/kg), or gentamicin (5 mg/kg). An untreated control group received 0.9% sodium chloride instead of antibiotic. Plasma endotoxin activity, blood bacteria count, and mean arterial pressure were monitored at 60-minute intervals for 5 hours. At the end of the experiment, lavage was performed to determine the bacteria count in the peritoneal cavity. RESULTS: In the untreated group, the blood bacteria count increased rapidly. Five hours after therapy, the plasma endotoxin activity in the cefotaxime group was higher by a factor of 3.6 than in the untreated group. Compared with the cefotaxime group, endotoxin activity was approximately 26% lower in the ciprofloxacin (3 mg/kg) group, 35% lower in the imipenem groups, and 38% lower in the gentamicin group. The lowest endotoxin levels were in the high-dose ciprofloxacin group. Bacteria counts in the peritoneal cavity were lowest in the gentamicin and high-dose ciprofloxacin groups. Except in the high-dose ciprofloxacin group, the endotoxin increase in the therapy groups was associated with a significant (P < .05) decrease in mean arterial pressure. CONCLUSIONS: In the early phase of therapy, antibiotic-induced endotoxin release is influenced by the mode of action of the agent class. This is not the sole influence in every class. With quinolones, this effect is also influenced considerably by dosage, ie, by pharmacodynamics.

Animals↗
PubMed1999

Cotton dust and endotoxin exposure and long-term decline in lung function: results of a longitudinal study.

BACKGROUND: To evaluate the relationship between long-term exposure to cotton dust and Gram-negative bacterial endotoxin on lung function, we conducted an 11-year follow-up study of cotton textile workers in Shanghai, China. METHODS: Workers at a nearby silk-thread manufacturing mill were used as a referent population. Ninety percent of the original cohort of 445 cotton and 467 silk textile workers--both active and retired--were identified for testing in the 11th year. Questionnaires and spirometric testing were performed, as well as cotton dust and endotoxin sampling at three points over the 11-year follow-up period: at baseline, at Year 5, and at Year 11. After excluding deaths and subjects on sick-leave, 84% of the original cohort had complete health and environmental data. RESULTS: The data were reanalyzed using generalized estimating equations feedback model which allow for subject transfer over time between work areas, various exposure levels to dust and endotoxin, and FEV1. Cotton workers had a larger loss of FEV1 during the first 5 years of study (-40 mls/yr) as compared with the second 6 years of follow-up (-18 mls/yr). During the same periods, the average decline among silk workers was slightly higher in the first period, but was more consistent (-30 mls/yr vs. -27 mls/yr), and these differences could not be explained by worker selection or dropout. When cumulative exposure to dust and endotoxin were estimated and used in a multivariate model (GEE) for FEV1 loss, cumulative dust, but not endotoxin, was associated with 11-year loss in FEV1 after adjustments for confounders. There was evidence of feedback between dust-exposure levels and FEV1, indicating the existence of a healthy-worker survivor effect. After accounting for a healthy-worker survivor effect, we found a significant relationship between dust exposure and FEV1 decline. CONCLUSIONS: Our results suggest that cotton dust is more strongly associated with chronic airflow limitation than associated endotoxins. Further work is needed to clarify potential reversibility after cessation of exposure, and the relative contributions of dust, endotoxin, and tobacco to chronic respiratory impairment in cotton and other vegetable-exposed workers.

Case-Control Studies↗
PubMed2006

Recombinant factor C assay for measuring endotoxin in house dust: comparison with LAL, and (1 --> 3)-beta-D-glucans.

BACKGROUND: Measurement of exposure to environmental endotoxin is frequently performed using a Limulus amebocyte lysate (LAL) based assay. Recently, a new method has become available with similar sensitivity and potentially greater specificity using recombinant Factor C (rFC) from the horseshoe crab Carcinoscorpius rotundicauda. A preliminary study was carried out to determine the comparability of LAL and rFC in measuring endotoxins in house dust for large scale epidemiologic studies. METHODS: House dust samples were collected from family rooms by vacuuming 1 m2 of the center of the room. Sixty sieved house dust samples were assayed for endotoxin by LAL (Cambrex, KQCL lysate) and rFC (Pyrogene, Cambrex) and for (1 --> 3)-beta-D-glucans by ELISA. The resistant parallel line estimation was used for data analysis of LAL and rFC. A four-parameter logistic fit with inverse prediction was used to calculate (1 --> 3)-beta-D-glucan levels of the samples. RESULTS: The spike recovery was 113.63% (95% CI = 101.69, 125.57%) for LAL and 99.69% (95% CI = 90.14, 109.24%) for rFC assays. The LAL assay gave higher endotoxin estimates compared with rFC. The LAL and rFC estimates were highly correlated (r = 0.86, P < 0.0001). The difference between LAL and rFC endotoxin estimates correlated with the LAL estimates (r = 0.51, P < 0.0001). However, the difference was not correlated with (1 --> 3)-beta-D-glucans. CONCLUSION: LAL and rFC gave comparable results, hence either assay can be used for studies of endotoxin exposure. The current study shows that (1 --> 3)-beta-D-glucan is not a major factor interfering with endotoxin measurements in house dust using a Cambrex KQCL LAL preparation.

Air Microbiology↗
PubMed2006

History and results of the two inter-laboratory round robin endotoxin assay studies on cotton dust.

BACKGROUND: In the US cotton industry, airborne cotton dust levels are regulated, and other countries are moving to specify safety limits for airborne endotoxins. There is concern about potential respiratory health hazards associated with agricultural and other organic dusts. In laboratories, ranking which samples have high and low levels of endotoxin is usually in good agreement between laboratories. When different laboratories assay identical samples, the levels differ. The objective of this research was to evaluate the intra- and inter-laboratory variability for 13 laboratories measuring endotoxin in cotton dust. METHOD: Two inter-laboratory round robin endotoxin assay studies were conducted using cotton dust. In the first round robin, each laboratory used their normal in-house assay method and then used a common extraction protocol. In the second round robin, a common extraction protocol and endotoxin assay kit was used. RESULTS: The intra-laboratory results had small variations but inter-laboratory results had very high variations. The inter-laboratory results using a common extraction protocol showed reduced differences. Using the same extraction protocol and endotoxin assay kit, the intra-laboratory variation was small and inter-laboratory variation was reduced but not enough for inter-laboratory agreement. Most of the laboratories were able to discern between the high and low endotoxin concentration dusts. CONCLUSIONS: Standardization has reduced the differences in results between laboratories and possibly further standardization may bring closer inter-laboratory agreement.

Air Microbiology↗
PubMed2006

Occupational endotoxin-exposure and possible health effects on humans.

BACKGROUND: Endotoxins are commonly found at workplaces where large amounts of bioaerosols are generated. In Germany, especially since the Ordinance on Safety and Health Protection related to work involving biological agents (Biostoff-Verordnung) became effective (1999), threshold limit values are widely discussed. Up to the present, endotoxin values are measured with non-uniform methods and therefore values are of limited benefit for classification of exposure groups. In Germany there is no threshold limit value for endotoxin. METHODS: Relevant literature of the last 20 years was selected from Medline and discussed. RESULTS: In this review we focused on the impact of endotoxin exposure on human health with special respect to the measurements on workplace and methodological aspects of endotoxin determination. Methods for sampling and endotoxin determination have to be validated, optimized, and standardized first. CONCLUSION: The adverse health effects of endotoxins are known, standardization of measurements is a necessary goal and protection measures should be established immediately.

Agriculture↗
PubMed1993

Cotton dust and gram-negative bacterial endotoxin correlations in two cotton textile mills.

Exposure to cotton dust is known to cause both acute and chronic respiratory illness. A specific pattern of symptoms called byssinosis is well described to occur among workers in the cotton processing (e.g., yarn preparation) industry. Recent studies have implicated Gram-negative bacterial endotoxin as one of the agents responsible for acute, and possibly chronic, respiratory illness. Laboratory experiments using a model cardroom have found poor correlations between airborne dust and associated endotoxin. This study reports the results of vertical elutriated dust and endotoxin levels in 11 work areas of 2 cotton textile mills in 1986 in Shanghai, China. The overall correlation between dust and endotoxin was strong, rs = 0.66 and 0.79 (p < 0.0001) for mills 1 and 2, respectively. The dust-endotoxin correlation was relatively poor in early yarn preparation in the workshops and improved in the later preparation areas. Our findings suggest that in these mill settings, dust and endotoxin levels may be well correlated in most work areas. Therefore, dust may be a useful index for monitoring populations employed in the cotton textile industry throughout the world. Additional field studies need to be performed which consider the various determinants of dust and endotoxin levels.

Air Pollutants, Occupational↗
PubMedDate not supplied

Effect of endotoxin on fibronectin and Kupffer cell activity.

The phagocytic activity of the reticuloendothelial system (RES) in the liver is important in host resistance to shock. Fibronectin is a large molecular weight glycoprotein which influences particulate uptake by phagocytic cells. This study addressed the effect of repeated low-dose endotoxin challenge on immunoreactive fibronectin and reticuloendothelial phagocytic function in rats. Intravenous Escherichia coli endotoxin increased circulating immunoreactive fibronectin by 100% within 24 hr; normalization was within 96 hr. Elevated fibronectin levels at 48 hr were associated with increased plasma opsonic activity as tested by liver slice phagocytic assay and RES stimulation, and in vitro uptake of gelatinized target particles by Kupffer cells in liver slices from endotoxin treated rats was significantly increased. Endotoxin tolerance was produced by repeated low dose challenge with endotoxin for 7 days and was associated with RES stimulation, even though the circulating fibronectin concentrations had returned to normal. By immunofluorescence, insoluble fibronectin was widely distributed in the liver in a pattern analogous to the sinusoidal vascular network. We suggest that increased RES phagocytic activity after low dose endotoxin challenge is due to early elevation of plasma fibronectin and cellular stimulation of phagocytic function followed by a sustained stimulation of Kupffer cells in the presence of normal fibronectin levels. Both cellular and humoral factors may contribute to increased Kupffer cell phagocytic activity during endotoxin tolerance.

Animals↗
PubMed2005

Does endotoxin contribute to aseptic loosening of orthopedic implants?

Aseptic loosening of orthopedic implants caused by wear particles is a major clinical problem. This review examines the hypothesis that bacterial endotoxin contributes to aseptic loosening. Clinical findings support this hypothesis: bacterial biofilms exist on many implants from patients with aseptic loosening and antibiotics in bone cement reduce the rate of aseptic loosening. Three approaches were used to demonstrate that adherent endotoxin increases bioactivity of titanium particles. These experiments measured cytokine production and osteoclast differentiation in vitro and murine calvarial osteolysis in vivo. First, removal of >99.9% of the adherent endotoxin from titanium particles significantly ablates their biological activity. Second, adding lipopolysaccharide back to these "endotoxin-free" particles restores their biological activity. Third, cells or mice that are genetically hyporesponsive to endotoxin are significantly less responsive to titanium particles than are wild-type controls. Other investigators have confirmed and extended these results to include virtually all orthopedically relevant types of particles, including authentic titanium alloy particles retrieved from patients with loosening. Our recent studies suggest that adherent endotoxin on orthopedic implants may also inhibit initial osseointegration of the implants. Taken together, these studies suggest that bacterial endotoxin may have a significant role in induction of aseptic loosening.

Animals↗
PubMed1992

A new sensitive microplate assay of plasma endotoxin.

We have developed a microplate method for determining endotoxin in platelet-rich plasma-using Endospecy, an endotoxin-specific chromogenic Limulus test reagent. Nonspecific activators and inhibitors of the test were eliminated by exposing samples (5 microliters) to the alkali reagent consisting of KOH, CaCl2, Triton X-100, ethyleniminepolymer and N,N-bis(2-hydroxyethyl)glycine. The recoveries of various endotoxins were almost complete and not enhanced by dilution. The dose-response curve was linear over endotoxin concentrations of 2-400 pg/ml with good precision (C.V. less than 5.0%). Normal human plasmas (n = 30) contained less than 5.0 pg/ml of endotoxin in reference to that of Escherichia coli 0111: B4. All plasma samples with high concentration of endotoxin by a conventional method showed high values by the microplate assay as well. Since it does not require centrifugation, the new treatment allows the whole reactions to proceed on the same microplate. This permits us to apply the Limulus test to an automated assay system, making plasma endotoxin determination simpler and more rapid than a conventional test tube method.

Detergents↗
PubMed1994

Cell-free hemoglobin reverses the endotoxin-mediated hyporesponsivity of rat aortic rings to alpha-adrenergic agents.

Hemoglobin (Hbg) and lysates of red blood cells act as vasoconstrictors in isolated vessels by a mechanism that may involve nitric oxide (NO.) scavenging. To determine if such a mechanism indeed occurs, we investigated the effects of cell-free Hgb, modified Hgp (met Hgb and cyan met Hgb), and red blood cells on the formation of NO. induced by endotoxin in rat aorta. Incubation of rat aortic rings with endotoxin induced a delayed and prolonged release of NO. that resulted in a decrease in the contractile response to phenylephrine. Hgb significantly potentiated contractions to phenylephrine in control rings and also reversed the hyporeactivity to this alpha 1-agonist in endotoxin-treated rings with and without endothelium. Lysed red blood cells but not whole red blood cells shifted the concentration-contraction response curves to phenylephrine significantly to the right in endotoxin-treated preparations. Neither picket-fence porphyrin-albumin (PFP-albumin) or metheme-albumin affected the contractile response to phenylephrine. Oxidation of Hgb to met Hgb did not alter the contractions to an alpha 1-agonist in endotoxin-treated rings. In contrast, the formation of cyan met Hgb abolished the action of Hgb on the vascular reactivity of endotoxin-treated preparations. Together, these results demonstrate that free Hgb can scavenge NO. produced in endotoxin-treated vascular tissue and that the ability to bind NO. requires a cell-free form of Hgb with an intact heme center capable of undergoing redox reactions.

Adrenergic alpha-Antagonists↗