Shwartzman Reaction In Rabbits Research Articles

The Fibrin Intermediate, Its Place in the Fibrinogen‐Fibrin Transformation

Our preceding study indicated that, in course of coagulation of human fibrinogen by thrombin, substantial production of the fibrin intermediate (alpha-profibrin) lacking only one fibrinopeptide A (FPA) precedes the formation of alpha-fibrin monomer lacking both FPAs. The plateau concentration of alpha-profibrin (20% of initial fibrinogen) appearing in reactions indicated, however, that the second FPA is released four times faster than the first. The study reported here confirms those findings, and provides new insight into the significance of differing rate constants for the production of alpha-profibrin and its conversion to alpha-fibrin. The intermediate could be isolated in a distinct electrophoretic band by electrophoresing partial thrombin digests at high concentrations. Its identity was verified by digesting it with CNBr and by demonstrating that its N-terminal domain, the NDSK fragment, both lacks an FPA and contains an FPA, unlike the NDSKs of the bands from fibrin which contained no FPA or the fibrinogen band that lacked no FPA. The single step isolation also enabled us to confirm the 15-20% plateau level of alpha-profibrin in course of thrombin reactions, well below the 37% maximum that would be expected if release of the first and second FPA proceeded independently with no difference in rate. The 37% maximum is observed in reactions with atroxin, and it is suggested that the abundant production of alpha-profibrin underlies the therapeutic utility of atroxin as a defibrinating agent. Gel chromatography procedures were optimized for isolation of alpha-profibrin/fibrin mixtures free of fibrinogen, the final step of which involves literal use of agarose gel as a filter to remove fibrin aggregates from the fibrinogen free fractions (aggregates are left behind in gel filtration, rather than their moving ahead in gel chromatography). Unlike human fibrinogen, rabbit fibrinogen does not yield much alpha-profibrin in course of its conversion to fibrin, less than 10% as determined by electrophoresis and comparison with abundant production with atroxin. This low production of alpha-profibrin conformed with conclusions from our early studies on the generalized Shwartzman reaction in rabbits, and we now infer that the low production of alpha-profibrin and rapid conversion to fibrin by rabbit fibrinogen underlies the unparalleled susceptibility of these animals toward fibrinoid formation in the generalized Shwartzman reaction.

Low endotoxic potential of Legionella pneumophila lipopolysaccharide due to failure of interaction with the monocyte lipopolysaccharide receptor CD14.

Legionella pneumophila, a gram-negative bacterium causing Legionnaires' disease and Pontiac fever, was shown to be highly reactive in in vitro gelation of Limulus lysate but not able to induce fever and the local Shwartzman reaction in rabbits and mice. We analyzed the capacity of purified L. pneumophila lipopolysaccharide (LPS-Lp) to induce activation of the human monocytic cell line Mono Mac 6, as revealed by secretion of proinflammatory cytokines and desensitization to subsequent LPS stimulation. We showed that despite normal reactivity of LPS-Lp in the Limulus amoebocyte lysate assay, induction of cytokine secretion in Mono Mac 6 cells and desensitization to an endotoxin challenge required LPS-Lp concentrations 1,000 times higher than for LPS of Salmonella enterica serovar Minnesota. Therefore, we examined the interaction of LPS-Lp with the LPS receptor CD14. We demonstrated that LPS-Lp did not bind to membrane-bound CD14 expressed on transfected CHO cells, nor did it react with soluble CD14. Our results suggest that the low endotoxic potential of LPS-Lp is due to a failure of interaction with the LPS receptor CD14.

In vivo neutralization of tumor necrosis factor attenuates the generalized Shwartzman reaction in the rabbit

A role for tumor necrosis factor (TNF) and TNF-induced tissue factor (TF) expression has been postulated in endotoxin (LPS)-induced diffuse intravascular coagulation (DIC). We studied the protective efficacy of goat polyclonal gammaglobulin (lgG) against recombinant human (rh)-TNF in the generalized Shwartzman reaction (GSR) in rabbits, a model of DIC. Administration of anti-rhTNF 2 h before the first, preparative, LPS injection afforded 95% neutralization of TNF released during the GSR. Compared to saline-pretreated controls, a modest attenuation of fibrin deposition in kidney, lung, liver and spleen was observed 4 h after the second provocative LPS injection. Except for the lung, fibrin deposition in the anti-rhTNF group was not attenuated compared to the non-immune goat IgG (ni-lgG)-pretreated group. Both ni-lgG and anti-rhTNF prevented LPS-induced TF expression by mononuclear cells, but not by isolated glomeruli. Other mediators than TNF and TF are involved as well in glomerular injury and fibrin deposition after LPS.

Local skin reactivity after induction of Shwartzman reaction in rabbits.

A local Shwartzman response was elicited in rabbits by an intradermal injection of the Salmonella typhosa endotoxin lipopolysaccharide (LPS) followed 24 hours later by an intravenous challenge injection with zymosan. After the intravenous challenge, necrotizing vasculitis developed in the prepared skin sites which was characterized by microthrombi, accumulation of neutrophil granulocytes, fibrin deposition and extravasation of red blood cells. Evans' blue extravasation into the altered tissue was significantly reduced, and histologically, the intensity of the Shwartzman reaction in the skin was reduced by pretreatment with thalidomide and dexamethasone. The mechanism of reduction of an LPS-induced local Shwartzman reaction by thalidomide is discussed.

Chemical, immunobiological and antigenic characterizations of lipopolysaccharides from Bacteroides gingivalis strains

Lipopolysaccharides (LPS) were extracted from whole cells of seven strains of Bacteroides gingivalis--381, ATCC 33277, BH18/10, OMZ314, OMZ406, 6/26 and HW24D-1--by the phenol/water procedure, and purified by treatment with nuclease and by repeated ultracentrifugation. These LPS were composed of hexoses, hexosamines, fatty acids, phosphorus and phosphorylated 2-keto-3-deoxyoctonate (KDO). The major components of the lipid portion of these LPS were hexadecanoic, 3-hydroxyhexadecanoic, branched 3-hydroxypentadecanoic and branched 3-hydroxyheptadecanoic acids. All the LPS preparations induced marked mitogenic and in vitro polyclonal B cell activation responses in spleen cells from both C3H/HeN and C3H/HeJ mice, exhibited no definitive preparatory activity in the local Shwartzman reaction in rabbits, but were active in the chromogenic Limulus amoebocyte lysate test. A monoclonal antibody (mAb) raised against the LPS from B. gingivalis strain 6/26 reacted with LPS from all other B. gingivalis strains tested. Other mAbs raised against LPS from B. gingivalis strains 381 and 6/26 reacted with the LPS from strains 381, ATCC 33277, BH18/10 and 6/26 (these strains were termed LPS serogroup I), as revealed by ELISA and immunodiffusion. The LPS from these strains except for 6/26 showed almost identical patterns in SDS-PAGE stained with ammoniacal silver. A mAb raised against the LPS from B. gingivalis HW24D-1 reacted with the LPS from strains OMZ314, HW24D-1 and OMZ409 (LPS serogroup II). These LPS, except OMZ409, exhibited very similar profiles in SDS-PAGE. These results indicate that there are at least two different antigenic groups present among LPS from B. gingivalis strains, as well as a common, species-specific antigen.

Biological activities of chemically synthesized 2-keto-3-deoxyoctonic acid-(alpha 2----6)-D-glucosamine analogs of lipid A.

The mitogenicity, lethal toxicity, and Shwartzman reaction of three derivatives of chemically synthesized 2-keto-3-deoxyoctonic acid-linked 2,3-diacyloxyacylglucosamine-4-phosphate (KDO-GlcN-4-P) were determined. The compounds, A-301 (with di-3-hexadecanoyloxytetradecanoyl at the C-2 and C-3 positions), A-303 (di-3-tetradecanoyloxytetradecanoyl), and A-305 (3-dodecanoyloxytetradecanoyl and 3-tetradecanoyloxytetradecanoyl), induced a significant incorporation of [3H]thymidine into splenocytes of C57BL/6 mice. The compounds A-301 and A-303 showed lethality at a high dose of 50 micrograms per mouse in C57BL/6 mice sensitized with D-galactosamine, whereas A-305 caused toxicity even at a dose of 10 micrograms per mouse. However, the three compounds did not elicit the local Shwartzman reaction in rabbits. These findings indicate that the addition of 2-keto-3-deoxyoctonic acid enhances the mitogenic activity of 2,3-diacyloxyacylglucosamine-4-phosphate but does not affect the lethal toxicity and the induction of Shwartzman reaction.

Neutrophil function in an experimental model of hemolytic uremic syndrome.

To understand the role of neutrophil leukocytosis in hemolytic uremic syndrome, we studied the changes in neutrophil function in the modified generalized Shwartzman reaction in rabbits. This model resembles hemolytic uremic syndrome associated with endotoxemia. At the end of an endotoxin infusion, we observed leukopenia, thrombocytopenia, and a decrease in hematocrit associated with schistocytosis. Plasma B-glucuronidase levels increased and this was associated with a decrease in neutrophil content of the enzyme. The chemotactic index and neutrophil aggregation to zymosan-activated serum were impaired compared to controls. The neutrophil procoagulant content increased after endotoxin infusion. The serum creatinine concentration and proteinuria increased in the endotoxin-treated animals. The changes returned to normal by 48 h. Renal cortical malondialdehyde, a reflection of lipid peroxidation, was higher in the endotoxin-treated animals than in the controls. We have shown enzyme release by neutrophils, impairment of chemotaxis and aggregation, increased procoagulant content in neutrophils, and evidence of lipid peroxidation in renal cortical tissue in this model. These observations raise the possibility that leukocytes may have a role in the pathogenesis of the hemolytic uremic syndrome.

Immunobiological activities of synthetic lipid A analogs with low endotoxicity

Synthetic lipid A analogs, beta(1-6)glucosamine disaccharide 1,4'-bisphosphates, which possesses four tetradecanoyl groups at the 2- and 2'-amino, and 3- and 3'-hydroxyl groups (LA-17-PP), and each two of the (R)-3-hydroxytetradecanoyl and tetradecanoyl groups at the 2- and 2'-amino and 3- and 3'-hydroxyl groups, respectively (LA-18-PP), were far less endotoxic than synthetic (506, LA-15-PP) and bacterial Escherichia coli type lipid A's; neither compound showed any detectable lethal toxicity in chicken embryos or preparatory activity for the local Shwartzman reaction in rabbits. Also both compounds were only weakly pyrogenic and comparably less lethally toxic in galactosamine-loaded mice than the reference synthetic and bacterial lipid A's and a synthetic counterpart to biosynthetic lipid A precursor Ia (406, LA-14-PP). Nevertheless, LA-17-PP and LA-18-PP exhibited definite in vivo immunoadjuvant activity in mice, and the ability to induce a possible tumor necrosis factor and alpha/beta interferon in Mycobacterium bovis BCG and Propionibacterium acnes-primed mice, respectively, although these activities were weaker than those of the reference lipid A's. 4'-Monophosphate analogs of the above two test compounds exhibited neither endotoxic nor beneficial activities, but they showed remarkable in vitro bioactivities comparable to those of the corresponding bisphosphate compounds; the ability to activate the human complement system and the clotting enzyme cascade of horseshoe crab amoebocyte lysate, stimulatory effects on guinea pig and murine peritoneal macrophages, and murine splenocytes.

Synthetic lipid A with endotoxic and related biological activities comparable to those of a natural lipid A from an Escherichia coli re-mutant.

A synthetic compound (506), beta (1-6) D-glucosamine disaccharide 1,4'-bisphosphate, which is acylated at 2'-amino and 3'-hydroxyl groups with (R)-3-dodecanoyloxytetradecanoyl and (R)-3-tetradecanoyloxytetradecanoyl groups, respectively, and has (R)-3-hydroxytetradecanoyl groups at 2-amino and 3-hydroxyl groups, exhibited full endotoxic activities identical to or sometimes stronger than those of a reference lipid A from an Escherichia coli Re-mutant (strain F515). Endotoxic activities tested include pyrogenicity and leukopenia-inducing activity in rabbits, body weight-decreasing toxicity in normal mice, lethal toxicity in galactosamine-sensitized mice and chicken embryos, and the preparation and provocation of the local Shwartzman reaction in rabbits. Compound 406, a synthetic counterpart of a biosynthetic precursor of lipid A molecule, showed by contrast only weak activities in all of the above assay systems except for the lethality in galactosamine-loaded mice. This finding strongly suggests that the presence of acyloxyacyl groups at the C-2' and C-3' positions of the disaccharide backbone is one of the most important determinant structures of the lipid A molecule for exhibition of strong biological activities characteristic of lipopolysaccharide and its lipid A moiety. The activities of the corresponding 4'-monophosphate (compound 504) and 1-monophosphate (505) analogs were considerably less than those of the parent molecule 506 and the reference F515 lipid A. Regarding other biological activities, not only compound 506 but also compounds 504, 505, and 406 showed definite activities, sometimes comparable to those of F515 lipid A and other reference natural products. These are the activation of Tachypleus tridentatus amoebocyte clotting enzyme cascade and human complement via the classical pathway, mitogenic and polyclonal B-cell activation of murine splenocytes, stimulation of peritoneal macrophages in a guinea pig, enhancement of migration of human blood polymorphonuclear leukocytes, and induction of a serum factor that is cytostatic and cytocidal to L-929 cells in Mycobacterium bovis BCG-primed mice. Relative potencies of test synthetic compounds depended on the assay systems and varied from one system to another. Dephospho-compound 503 lacked most of the biological activities that were definitely observed with phosphorylated compounds, probably because of its insolubility. This study demonstrates the successful chemical synthesis of an E. coli-type lipid A.

The influence of renal sympathetic denervation on the generalized Shwartzman reaction in rabbit

The sympathetic denervation of the kidney resulted in a significantly diminished intraglomerular fibrin deposition during the generalized Shwartzman reaction in unanesthetized rabbit when 50 mcg/kg of endotoxin was given as the provocative dose by 4-hours' infusion or by i.v. injection. This effect of renal denervation was abolished when the provocative endotoxin dose was increased to 100 mcg/kg. It is supposed that the decrease of the intraglomerular fibrin deposition in the denervated kidney following infusion or injection of 50 mcg/kg of endotoxin is a result of the suppression of vasomotor action of endotoxin mediated via sympathetic neurons.

The effect of the stimulation of alpha or beta adrenergic receptors on the generalized Shwartzman reaction in rabbit with denervated kidney

The influence of alpha- or beta-adrenergic agonists on the endotoxin-induced intraglomerular fibrin deposition (i.f.d.) was studied in rabbits with one denervated kidney. The norepinephrine infused together with the provocative endotoxin dose did not influence i.f.d. within the denervated kidney or in the intact one. The isoproterenol administered also in a common infusion with provocative endotoxin dose had no effect on i.f.d. in the intact kidney but significantly augmented this deposition within the denervated kidney. The results of the fibrinolytic activity of kidney cortex cannot explain the effects of adrenergic agonists on endotoxin-induced i.f.d. It is supposed that the enhancing effect of isoproterenol on i.f.d. within the denervated kidney can be ascribed to the vasodilating effect of this drug, promoted in the denervated kidney by the absence of endogenous norepinephrine at the nerve endings.

The capacity of lipopolysaccharides from bacteroides, fusobacterium and veillonella to produce skin inflammation and the local and generalized Shwartzman reaction in rabbits.

Purified lipopolysaccharides (LPS) from strains of Bacteroides, Fusobacterium and Veillonella were tested for endotoxic activity, utilizing the primary skin reaction and the Shwartzman phenomena in rabbits. Comparisons were made to Salmonella LPS. Each LPS preparation produced the primary skin reaction in a typical dose‐response fashion. Skin sites injected with 400 μg of Fusobacterium LPS often produced necrotic lesions. In the comparisons made between the skin lesion doses (SLD50) of the Veitlonella LPS and the Salmonella LPS, the difference was either non‐significant or the Salmonella LPS was only slightly more active (P <0.02). LPS from the Fusobacterium and the Bacteroides were significantly less toxic than the Salmonella LPS (P <0.005). All LPS preparations did prepare the skin for the local and the specific organs for the generalized Shwartzman reaction. The toxicity of the Bacteroides LPS was, however, very low in the local reaction (P <0.005). For all LPS preparations the sensitivity of the primary skin test (SLD50) was superior to the local Schwartzman reaction (SPD50) (P <0.005).Twenty‐four hours after challenge for the generalized Shwartzman reaction, extensive fibrin thrombi in the capillaries of the renal glomeruli were found, as well as thrombi containing necrotic blood cells, both in the veins of the liver and in the arteries of the lungs.The high endotoxic activity of the Fusobacterium and the Veillonella LPS may reflect a similarity between their lipid A and that of the Salmonella LPS.

Biologic Properties of Nontoxic Derivatives of a Lipopolysaccharide from Escherichia Coli K235

Lipopolysaccharide (LPS)2 from Escherichia coli K235 was treated with o-phthalic anhydride to obtain a high degree of esterification of available hydroxyl groups, leaving a free carboxyl for each hydroxyl esterified (SPLPS). Although there was no demonstrable loss of fatty acids, this conversion of LPS to a polyanionic molecule altered dramatically the spectrum of biologic properties, most of which are normally attributed to the lipid A (LA) moiety. Mitogenicity for mouse B cells was decreased several hundred-fold; reaction with antibodies to LPS was abolished; pyrogenicity and toxicity were decreased by factors of 10(5) and 10(4); the ability to induce the Shwartzman reaction in rabbits was decreased 500-fold, and the ability to stimulate production of interferon in mice was decreased by more than 2 x 10(3). However, despite the loss of these properties, SPLPS retained the ability to act as an immunologic adjuvant. The nature of the anionic group is important, e.g., sodium succinyl-LPS (SuLPS) is 10-fold more pyrogenic and toxic than sodium phthalyl-LPS (SPLPS). Data on another LPS derivative, from which ester-linked fatty acid residues were removed before phthalylation, suggest that the ester-linked fatty acid groups in the lipid A moeity of SPLPS may not be necessary for its immunologic adjuvant effect.

The influence of large doses of hydrocortisone on the generalized Shwartzman reaction in rabbit

The influence of large doses (50 mg/kg) of hydrocortisone, given after both or only after second endotoxin dose, on the generalized Shwartzman reaction was studied. The effect of hydrocortisone alone was also investigated. The hydrocortisone injection after the first endotoxin dose lessened the decrease in platelet count but this effect was not observed after the second endotoxin dose. The addition of hydrocortisone to endotoxin did not change the pattern of fibrinogen concentration in plasma but did increase the frequency of positive ethanol gelation test. The Fibrinogen/Fibrin Related Antigen content in serum rose gradually throughout the experiments, especially in animals given hydrocortisone after both endotoxin doses. The injections of hydrocortisone alone inhibited fibrinolytic activity in euglobulins but did not change the content of plasminogen activator in the outer medullary zone of rabbit kidney. In comparison with results of previous studies on generalized Shwartzman reaction (Thrombos. Res.: 6 , 399, 1975), the addition of hydrocortisone to endotoxine increased the inhibition of fibrinolytic activity in euglobulins. The decrease of plasminogen activator content in the outer medullary zone of kidneys was less pronounced when first hydrocortisone injection followed the provocative endotoxin dose than after both injections of endotoxin and hydrocortisone. Injections of hydrocortisone following both doses of endotoxin increased fibrin deposition within kidney glomeruli. It is supposed that this effect is due to the inhibited release of tissue plasminogen activator in rabbit kidney after large doses of hydrocortisone.

Elicitation of the Generalized Shwartzman Reaction in Rabbits with Parenteral Iron Preparations and Bacterial Endotoxin

Some parenteral iron preparations were examined regarding their ability to act as preparing agents in the elicitation of the generalized Shwartzman reaction in the rabbit. As expression of the generalized Shwartzman reaction bilateral cortical necrosis of the kidneys was demonstrated when Imferon, Iroject, Macofer, and A 2152 were used as preparing agents. No renal lesion was observed when Jectofer was used.

Soluble fibrin monomer complexes and fibrinolytic activity in kidney during the generalized Shwartzman reaction in rabbit

The generalized Shwartzman reaction (GSR) was induced in rabbits. Blood samples were obtained at intervals and determinations were made of fibrinogen concentration, platelet count, soluble fibrin monomer complexes (SFMC) and the fibrinolytic activity of the euglobulin fraction. In addition, the tissue plasminogen activator activity in kidney sections was measured. An increase in SFMC and decrease in tissue activator activity in the outer medullary zone of the kidney were observed 6 hours after the preparative endotoxin dose as well as 3 and 6 hours after the provocative injection. The maximal fibrin deposition within the kidney glomeruli was observed 6 hours after the provocative endotoxin injection and 18 hours later the amount of intraglomerular fibrin decreased but the secondary, necrotic changes of the kidney cortex progressed. The fibrinolytic activity in the outer medullary zone of kidney returned to the normal values at the same time. The importance of the fibrinolytic activity in kidney as a defensive mechanism in GSR is discussed.

Chemical structure and biological activity of endotoxins (lipopolysaccharides) and lipid A.

Lipopolysaccharides (endotoxins) of gram-negative bacteria consist of two components with distinct physico-chemical character: a heteropolysaccharide and a covalently linked lipid, termed lipid A. Chemically, lipid A is made up of acylated glucosamine disaccharides, which are interlinked by pyrophosphate bridges. Lipid A represents the toxic center of lipopolysaccharides. In rabbits, lipid A also induces pyrogen tolerance as well as pyrogen cross-tolerance. Fever tolerance can be passively transferred with serum from rabbits immunized with lipid A. The protective power of lipid A antiserum, however, is only expressed in amimals which have been pretreated with lipid A or lipopolysaccharide, indicating that other than humoral factors, perhaps cellular, also participate in endotoxin tolerance. Lipid A antiserum also prevents the local Shwartzman reaction in rabbits. The possible potency of lipid A antiserum to prevent other endotoxin effects such as lethal shock is presently investigated.

Determinants and modification of adrenergic and vascular resistance in the kidney

ARTICLESDeterminants and modification of adrenergic and vascular resistance in the kidneyP Needleman, GR Marshall, and Johnson EM JrP Needleman, GR Marshall, and Johnson EM JrPublished Online:01 Sep 1974https://doi.org/10.1152/ajplegacy.1974.227.3.665MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByRenal Blood Flow1 January 2011Renal Prostaglandins and Other Eicosanoids1 January 2011Sexual Dimorphism of Cardiovascular Function: The Role of AndrogensPAF-induced bowel necrosisDigestive Diseases and Sciences, Vol. 36, No. 5Interactions between angiotensin II, sympathetic nerve-mediated pressor response and cyclo-oxygenase products in the pithed rat19 July 2012 | British Journal of Pharmacology, Vol. 95, No. 4Gonadectomy and hormonal replacement changes systolic blood pressure and ventricular myosin isoenzyme pattern of spontaneously hypertensive rats.Circulation Research, Vol. 63, No. 6Nonsteroidal Anti-Inflammatory Drugs and Renal Function8 March 2013 | The Journal of Clinical Pharmacology, Vol. 28, No. 6Sequential release of leukotrienes and norepinephrine in rat bowel after platelet-activating factorGastroenterology, Vol. 94, No. 6Renal prostaglandin production is increased during abdominal sepsis in the rat and unaffected by the infusion of different amino acid formulationsJournal of Surgical Research, Vol. 44, No. 2The clinical significance of inhibition of renal prostaglandin synthesisKidney International, Vol. 32, No. 1Effect of Norepinephrine and Angiotensin II on Intrarenal Oxygen AvailabilityA Possible Role of Gonad and Renal Prostaglandin E2 on the Development of Hypertension in Spontaneously Hypertensive Rats*Japanese Journal of Pharmacology, Vol. 37, No. 1Die Niere im Schock und Schockniere — Nosologie, Pathophysiologie, Klinik und TherapieProstaglandin actions on the adrenergic nervous systemKlinische Wochenschrift, Vol. 61, No. 11Sympathetic nervous activity, renin-angiotensin system and renal excretion of prostaglandin E 2 in cirrhosis. 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Implication of vascular angiotensin II in hypertension and antihypertensive actions of captopril.Hypertension, Vol. 3, No. 3_pt_2Influence of prostaglandins on vasoconstrictor responses in the hindquarters vascular bed of the catProstaglandins and Medicine, Vol. 6, No. 2Reversal of corticosterone-induced supersensitivity of vascular smooth muscle to noradrenaline by arachidonic acid and prostacyclinEuropean Journal of Pharmacology, Vol. 68, No. 3The effect of the stimulation of alpha or beta adrenergic receptors on the generalized Shwartzman reaction in rabbit with denervated kidneyThrombosis Research, Vol. 12, No. 2The Effects of Salt and Meclofenamate Administration on the Hypertension of Spontaneously Hypertensive Rats3 July 2009 | Clinical and Experimental Hypertension, Vol. 1, No. 3The Effect of Indomethacin on Renal Blood Flow Distribution during Hemorrhagic Hypotension in DogActa Physiologica Scandinavica, Vol. 101, No. 1THE EFFECT OF PHENOXYBENZAMINE AND SARALASIN ON THE ALTERED RENAL BLOOD FLOW DISTRIBUTION IN BABOONS WITH OBSTRUCTIVE JAUNDICEClinical and Experimental Pharmacology and Physiology, Vol. 4, No. 4Influence of prostaglandin E2, indomethacin, and reserpine on renal vascular responses to nerve stimulation, pressor and depressor hormones.Circulation Research, Vol. 41, No. 2Shock and the kidney: Pathophysiology and pharmacological supportIntensive Care Medicine, Vol. 3, No. 1Pharmacology of the renal circulationThe American Journal of Medicine, Vol. 62, No. 4Influence of inhibitors of prostaglandin synthesis on renal vascular resistance and on renal vascular responses to vasopressor and vasodilator agents in the cat.Circulation Research, Vol. 40, No. 4Prostaglandins: Effects on blood pressure, renal blood flow, sodium and water excretionKidney International, Vol. 10, No. 3Genetic hypertension in rats is accompanied by a defect in renal prostaglandin catabolismNature, Vol. 260, No. 5552 More from this issue > Volume 227Issue 3September 1974Pages 665-669 Copyright & PermissionsCopyright © 1974 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1974.227.3.665PubMed4369912History Published online 1 September 1974 Published in print 1 September 1974 Metrics

Prevention of the generalized Shwartzman reaction and endotoxin lethality by polymyxin B localized in tissues.

Pretreatment with multiple doses of polymyxin B and colistimethate was evaluated as to its ability to sequester sufficient antibiotic in tissues to neutralize the effects of endotoxin in three animal models. Animals were challenged with endotoxin 24, 48, or 72 h after the last dose of antibiotic when there was minimal or not detectable drug in serum. Pretreatment with polymyxin B was successful in preventing the generalized Shwartzman reaction in rabbits and reducing endotoxin lethality in mice; however, large doses (20 mg per kg per day for 2 or 4 days) were required. Prolongation by more than 24 h of the interval between the last dose of polymyxin B and endotoxin challenge resulted in reduction or loss of protection. Dogs were unable to tolerate the high polymyxin B dosage which was protective in the mouse and rabbit. Lower, nontoxic doses of polymyxin B in dogs did not prevent endotoxin shock and lethality, even when challenged as soon as 1 h after the last dose. Pretreatment with colistimethate was ineffective in all three animal models.

Production of the generalized Shwartzman reaction in rabbits by ancrod ('Arvin') infusion and endotoxin injection.

Summary. The effect of the coagulant fraction from Agkistrodon rhodostoma venom (Arvin = ancrod) on the generation of microthrombi was studied in rabbits. Ancrod infusion caused hypofibrinogenaemia and induced the formation of circulating fibrin monomer complexes, but microthrombi were not detected in the glomerular capillaries. If, however, endotoxin was injected into ancrod‐infused rabbits, 73% of the animals showed microclots in the glomerular capillaries typical of the generalized Shwartzman reaction. These microclots exhibited antigenic characteristics of fibrinogen derivatives. Injection of endotoxin only did not produce glomerular capillary thrombosis and the mean fibrinogen levels did not decrease significantly, although fibrin monomer complexes could be detected in all the rabbits. Generation of microthrombosis by ancrod infusion and endotoxin injection could not be prevented by treating the animals with heparin. Thus endotoxin mediated the generation of microclots in ancrod‐infused rabbits by a mechanism different from its procoagulant activity. Heparin treatment interfered neither with the decrease in fibrinogen levels caused by ancrod infusion nor with the fall in the platelet counts caused by endotoxin injection.