Action of histamine and its receptor blockers on uterine circulation in sheep.

Effects of iv and ia administration of histamine and its H1 and H2 blockers (diphenhydramine and metiamide) on systemic arterial pressure, heart rate, and uterine and iliac blood flows were investigated in unanesthetized, chronically instrumented nonpregnant ewes. Intravenous histamine produced tachycardia, hypotension, and decreased iliac and uterine blood flows. In contrast, ia injections produced a significant increase in blood flows in these vascular beds which was dose-dependent. Evidence is presented to show that some of the circulatory actions of histamine may be related to stimulation of H1 while others may be related to H2 receptors. The peripheral circulatory action produced by iv histamine is probably secondary to its effects on reducing cardiac output. The uterine and iliac vascular beds contain mostly H1 receptors since their response to histamine can be blocked almost totally by Benadryl and not by H2 antagonist metiamide.     

Acetaldehyde induces histamine release from purified rat peritoneal mast cells

Acetaldehyde is a widely distributed compound in the human environment and it is also formed in the human body from various endogenous and exogenous sources, exogenous ethanol being the most important one. Many alcohol-associated hypersensitivity reactions, e.g. Oriental flushing reaction, appear to be attributable to acetaldehyde rather than to ethanol itself. The pathogenetic mechanism behind such hypersensitivity reactions has been suggested to be histamine release from mast cells or blood basophils. However, the direct effects of acetaldehyde on mast cells, the main source of histamine in a mammalian body, have not been studied. The aim of the present study was, thus, to evaluate whether physiological concentrations of acetaldehyde could release histamine from purified rat peritoneal mast cells. The effects of ethanol were studied similarly. The results show that acetaldehyde, already at a concentration of 50 microM, significantly increases the release of histamine from mast cells. Ethanol has a similar effect but only at molar concentrations. These results indicate that acetaldehyde may contribute to the development of various hypersensitivity reactions by directly increasing histamine release from mast cells.     

Fullerene nanomaterials inhibit the allergic response

Fullerenes are a class of novel carbon allotropes that may have practical applications in biotechnology and medicine. Human mast cells (MC) and peripheral blood basophils are critical cells involved in the initiation and propagation of several inflammatory conditions, mainly type I hypersensitivity. We report an unanticipated role of fullerenes as a negative regulator of allergic mediator release that suppresses Ag-driven type I hypersensitivity. Human MC and peripheral blood basophils exhibited a significant inhibition of IgE dependent mediator release when preincubated with C(60) fullerenes. Protein microarray demonstrated that inhibition of mediator release involves profound reductions in the activation of signaling molecules involved in mediator release and oxidative stress. Follow-up studies demonstrated that the tyrosine phosphorylation of Syk was dramatically inhibited in Ag-challenged cells first incubated with fullerenes. In addition, fullerene preincubation significantly inhibited IgE-induced elevation in cytoplasmic reactive oxygen species levels. Furthermore, fullerenes prevented the in vivo release of histamine and drop in core body temperature in vivo using a MC-dependent model of anaphylaxis. These findings identify a new biological function for fullerenes and may represent a novel way to control MC-dependent diseases including asthma, inflammatory arthritis, heart disease, and multiple sclerosis.     

Histamine release and SOD, allopurinol and ranitidine pretreatment in haemorrhagic shock in the rat.

Histamine release have been demonstrated in haemorrhagic shock. There are some observations that oxygen free radicals can cause histamine release. Oxygen free radicals play a role in the pathogenesis of gastric mucosal lesions. The goal of this study was to determine whether ranitidine or SOD and allopurinol pretreatment modify the histamine release during and after the haemorrhagic shock in the rat. In the anaesthetized rat 0.1 N HCl was instilled into the stomach and the rat was bled to reduce the blood pressure to 30 mmHg for 20 min. The shed blood was reinfused. Twenty min later the stomach was removed. The area of gastric mucosal lesions were measured, histological grading was made. Blood samples taken from the carotid artery were examined by radioimmunoassay (IMMUNOTECH) to determine the plasma histamine level. Plasma histamine level did not change significantly during the preparative surgery, but there was a significant increase of histamine level by the end of shock period. After the reinfusion of the blood the plasma histamine remained essentially at the same level for five min. Oxygen free radicals did not cause an important histamine release. By the end of the experiment the histamine level decreased dramatically. Ranitidine, allopurinol and SOD pretreatment provided significant protection against the gastric mucosal lesions. Allopurinol and SOD did not influence significantly the histamine level. Ranitidine caused significant histamine release immediately after the injection and every histamine value was significantly higher in this group except for the final value which was lower than the control one. The oxygen free radicals were not found as endogenous histamine releasers in this study.     

内源性一氧化碳在大鼠败血症性休克时 低血压发生机制中的作用

A sepsis model induced by cecal ligation and puncture was used to study the role of endogenous carbon monoxide in hypotension pathogenesis of rats during septic shock. After administration of zinc deuteroporphyrin 2,4-bisglycol (ZnDPBG),an inhibitor of heme oxygenase (HO),blood pressure (BP),HO activity and carbon monoxide (CO) release from vascular muscle tissue were measured. The results showed that BP of sepsis rats,including systolic and diastolic arterial BP,decreased significantly while HO activity and CO content were significantly increased. In contrast,after administration of ZnDPBG,BP of sepsis rats was significantly increased while the HO activity and CO production were significantly decreased. These findings suggest that HO activity and CO release within vascular musculature are increased during septic shock;inhibition of HO may elevate BP of rats during septic shock through a decrease of endogenous CO production. It is concluded that endogenous CO derived from vascular muscle cells plays an important role in regulating vascular tone,and the up-regulation of HO activity followed by subsequent CO production contributes to hypotension pathogenesis during septic shock.     

内源性一氧化碳在大鼠败血症性休克时低血压发生机制中的作用

应用盲肠结扎法制备大鼠败血症休克模型,研究内源性一氧化碳（ＣＯ）在败血症休克时低血压发病中的作用。用血红素加氧酶（ｈｅｍｅｏｘｙｇｅｎａｓｅ,ＨＯ）抑制剂２,４二甘油次卟啉锌（ｚｉｎｃｄｅｕｔｅｒｏｐｏｒｐｈｙｒｉｎ２,４ｂｉｓｇｌｙｃｏｌ,ＺｎＤＰＢＧ）处理大鼠后,观察动物动脉血压,同时测定主动脉平滑肌组织中ＨＯ活性和ＣＯ生成量。结果发现：败血症大鼠动脉收缩压、舒张压降低,同时血管平滑肌ＨＯ活性和ＣＯ生成明显增加。败血症大鼠用ＺｎＤＰＢＧ处理后,动脉血压明显回升,同时ＨＯ活性和ＣＯ生成明显被抑制。实验表明败血症休克时低血压的发生与血管平滑肌细胞ＨＯ活性增加和内源性ＣＯ生成增多明显相关;应用ＨＯ抑制剂阻断ＨＯ活性能导致内源性ＣＯ生成减少,继而使败血症休克时大鼠血压明显回升。实验提示,内源性ＣＯ对血管张力具有重要的调节作用;ＨＯ活性和内源性ＣＯ生成增加是败血症休克时低血压发生的重要机制之一。     

内源性一氧化碳在大鼠败血症休克时低血压发生机制中的作用

A sepsis model induced by cecal ligation and puncture was used to study the role of endogenous carbon monoxide in hypotension pathogenesis of rats during septic shock. After administration of zinc deuteroporphyrin 2,4-bisglycol (ZnDPBG),an inhibitor of heme oxygenase (HO),blood pressure (BP),HO activity and carbon monoxide (CO) release from vascular muscle tissue were measured. The results showed that BP of sepsis rats, including systolic and diastolic arterial BP, decreased significantly while HO activity and CO content were significantly increased. In contrast, after administration of ZnDPBG, BP of sepsis rats was significantly increased while the HO activity and CO production were significantly decreased. These findings suggest that HO activity and CO release within vascular musculature are increased during septic shock; inhibition of HO may elevate BP of rats during septic shock through a decrease of endogenous CO production. It is concluded that endogenous CO derived from vascular muscle cells plays an important role in regulating vascular tone, and the up-regulation of HO activity followed by subsequent CO production contributes to hypotension pathogenesis during septic shock.     

Investigations into lymphocyte transformation and histamine release by basophils in sheep repeatedly infested with Rhipicephalus evertsi evertsi ticks

The immune response of a natural host of Rhipicephalus evertsi evertsi to feeding by this tick species was investigated with respect to the effects of tick salivary gland extracts on the transformation of peripheral blood lymphocytes and the release of histamine by basophils obtained from repeatedly infested sheep.The results indicated that there was no stimulation of lymphocyte transformation but that histamine release was elevated 10 fold after four infestations.Although this suggests a hypersensitivity reaction, believed to be a major factor in resistance to tick feeding, it was observed that ticks fed normally even after four infestations with 28 day intervals in between. These results emphasize the adaptation of ticks to feeding on their natural hosts.     

Interleukin-4 (IL-4) enhances and soluble interleukin-4 receptor (sIL-4R) inhibits histamine release from peripheral blood basophils and mast cells in vitro and in vivo

The aim of the study was to analyse the effect of interleukin-4 (IL-4) on allergen and anti-IgE mediated histamine release from basophils and human skin mast cells and to assess whether soluble recombinant interleukin-4 receptor (sIL4R) can inhibit these effects. Anti-IgE stimulated histamine release from peripheral blood basophils and mast cells of atopic donors was enhanced after preincubation with IL-4, whereas after preincubation with sIL-4R it was inhibited. These effects were even more pronounced when samples were stimulated with a clinically relevant allergen. In IL-4 preincubated skin mast cells, there was a similar enhancement of anti-IgE stimulated histamine release, which could again be inhibited by sIL-4R. The effects of IL-4 and sIL4R were dose- and time-dependent. Mice sensitized to ovalbumin and treated with soluble recombinant murine sIL-4R showed significantly reduced immediate-type cutaneous hypersensitivity responses compared with untreated mice. These in vivo effects were IgE independent, since there were no significant differences in total and allergen specific IgE/IgG1 antibody titres between treated and untreated mice. This indicates that IL4 exerts priming effects on histamine release by effector cells of the allergic response and that these effects are potently antagonized by soluble IL-4R both in vitro and in vivo.     

Histamine release from cultured human basophils: lack of histamine resynthesis after antigenic release.

Human peripheral basophils can be maintained in cultured for up to 72 hr. These cells retain their functional integrity as judged by total histamine content and by their ability to release histamine by an IgE-mediated reaction in response to a specific antigen challenge. Cells cultured after suboptimal antigenic challenge could be activated to release histamine upon the addition of antigen. In contrast, cells culture after supra-optimal antigenic challenge did not fully recover their ability to release histamine even after 24 hr. With a variety of culture conditions, it was impossible to demonstrate any net synthesis of histamine in cells. Cells cultured after depletion of their stores by reaction with antigen did not show any net histamine formation. The experiments suggest that the basophil in peripheral blood is functionally an end-stage cell and can participate in the histamine release reaction only once.     

Absorption and release of biogenic amines by the lung during the restorative period after hypovolemic hypotension

The processes of serotonin and histamine absorption and release by the lungs were studied in dogs during 1 to 3.5 hour hypovolemic hypotension and during 24 hours after blood retains fusion. Absorption of biogenic amines by the lungs tended to increase in all the animals under hypovolemic hypotension. In the group of non-survivors the serotonin absorption by the lungs in the post-terminal period remained increased, while in the group of survivors it came down to normal soon, though the histamine release was increased. The above processes were aggravated in the group of animals whose lungs were affected by oleic acid. It resulted in the absorption of histamine instead of its release. The intensified absorption of biogenic amines by the lungs was accompanied by a quick fall in cardiac output, by the increase in resistance of systemic and pulmonary circulation.     

Effect of antibiotics on immediate hypersensitivity reactions in vitro: suppression of IgE-mediated histamine release from peripheral blood basophils by fosfomycin

The effect of antibiotics on allergic reactions was studied in vitro using the release of histamine from human peripheral blood leukocytes (basophils) after incubation with anti-IgE. For the several antibiotics we tested, including beta-lactams and aminoglycosides, none had the capacity to enhance antigen-induced histamine release, but some of them (minocycline, polymyxin B, and fosfomycin) suppressed the release of histamine in a dose-dependent manner. Since fosfomycin has proved to be capable of suppressing IgE-mediated histamine release non-cytotoxically, the effect of fosfomycin on histamine release induced by other secretagogues was further studied. The suppression of histamine release was also demonstrated when the leukocytes, preincubated with fosfomycin, were challenged with either Ca ionophore A 23187 or a synthetic peptide, formyl-methionyl-leucyl-phenylalanine (FMLP). We concluded that some antibiotics, particularly fosfomycin, have the capacity to suppress histamine release mediated by various secretagogues, suggesting they may possess an anti-allergic property as well as a bactericidal activity.     

Animal Models of Complement-Mediated Hypersensitivity Reactions to Liposomes and Other Lipid-Based Nanoparticles

Intravenous injection of some liposomal drugs, diagnostic agents, micelles and other lipid-based nanoparticles can cause acute hypersensitivity reactions (HSRs) in a high percentage (up to 45%) of patients, with hemodynamic, respiratory and cutaneous manifestations. The phenomenon can be explained with activation of the complement (C) system on the surface of lipid particles, leading to anaphylatoxin (C5a and C3a) liberation and subsequent release reactions of mast cells, basophils and possibly other inflammatory cells in blood. These reactions can be reproduced and studied in pigs, dogs and rats, animal models which differ from each other in sensitivity and spectrum of symptoms. In the most sensitive pig model, a few miligrams of liposome (phospholipid) can cause anaphylactoid shock, characterized by pulmonary hypertension, systemic hypotension, decreased cardiac output and major cardiac arrhythmias. Pigs also display cutaneous symptoms, such as flushing and rash. The sensitivity of dogs to hemodynamic changes is close to that of pigs, but unlike pigs, dogs also react to micellar lipids (such as Cremophor EL) and their response includes pronounced blood cell and vegetative neural changes (e.g., leukopenia followed by leukocytosis, thrombocytopenia, fluid excretions). Rats are relatively insensitive inasmuch as hypotension, their most prominent response to liposomes, is induced only by one or two orders of magnitude higher phospholipid doses (based on body weight) compared to the reactogenic dose in pigs and dogs. It is suggested that the porcine and dog models are applicable for measuring and predicting the (pseudo)allergic activity of particulate “nanodrugs”.     

Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis

Septic shock is a life-threatening condition that results from exposure to bacterial endotoxin. It is manifested by cardiovascular collapse and mediated by the release of cytokines such as tumor necrosis factor. Some of these cytokines cause the release of vasoactive substances. In the present study, administration of 40 microgram/kg of bacterial endotoxin to dogs caused a 33% decrease in peripheral vascular resistance and a 54% fall in mean arterial blood pressure within 30 to 90 minutes. Vascular resistance and systemic arterial pressure returned to normal within 1.5 minutes after intravenous administration of NG-methyl-L-arginine (20 mg/kg), a potent and selective inhibitor of nitric oxide synthesis. L-Arginine reversed the effect of L-NMA and restored the endotoxin-induced hypotension. Although NG-methyl-L-arginine injection increased blood pressure in control dogs, the hypertensive effect was much greater in endotoxemic dogs (24.8 +/- 2.7 mmHg vs 47.8 +/- 6.8 mmHg, p = 0.01, n = 4). NG-Methyl-L-arginine caused only a modest increase in blood pressure in dogs made hypotensive by continuous intravenous infusion of nitroglycerin (17.1 +/- 5.0 mm Hg, n = 3). These findings suggest that nitric oxide overproduction is an important contributor to endotoxic shock. Moreover, our findings demonstrate for the first time, the utility of nitric oxide synthesis inhibitors in endotoxic shock and suggest that such inhibitors may be of therapeutic value in the treatment of septic shock.     

Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles

Intravenous injection of some liposomal drugs, diagnostic agents, micelles and other lipid-based nanoparticles can cause acute hypersensitivity reactions (HSRs) in a high percentage (up to 45%) of patients, with hemodynamic, respiratory and cutaneous manifestations. The phenomenon can be explained with activation of the complement (C) system on the surface of lipid particles, leading to anaphylatoxin (C5a and C3a) liberation and subsequent release reactions of mast cells, basophils and possibly other inflammatory cells in blood. These reactions can be reproduced and studied in pigs, dogs and rats, animal models which differ from each other in sensitivity and spectrum of symptoms. In the most sensitive pig model, a few miligrams of liposome (phospholipid) can cause anaphylactoid shock, characterized by pulmonary hypertension, systemic hypotension, decreased cardiac output and major cardiac arrhythmias. Pigs also display cutaneous symptoms, such as flushing and rash. The sensitivity of dogs to hemodynamic changes is close to that of pigs, but unlike pigs, dogs also react to micellar lipids (such as Cremophor EL) and their response includes pronounced blood cell and vegetative neural changes (e.g., leukopenia followed by leukocytosis, thrombocytopenia, fluid excretions). Rats are relatively insensitive inasmuch as hypotension, their most prominent response to liposomes, is induced only by one or two orders of magnitude higher phospholipid doses (based on body weight) compared to the reactogenic dose in pigs and dogs. It is suggested that the porcine and dog models are applicable for measuring and predicting the (pseudo)allergic activity of particulate "nanodrugs".     

Central histamine-induced reversal of critical haemorrhagic hypotension in rats--haemodynamic studies.

Volume-controlled irreversible haemorrhagic shock in rats produced by blood withdrawal until stabilisation of critical mean arterial pressure (MAP) 20-25 mmHg is associated with an extreme decrease in cardiac index (CI) and an increase in total peripheral resistance index (TPRI), with reductions in renal (RBF), hindquarters (HBF) and mesenteric blood flow (MBF), and leads to the death of all control animals within 30 min. Histamine (100 nmol) injected intracerebroventricularly (i.c.v.) in the early phase of critical hypotension produces a prompt and long-lasting increase in MAP and heart rate, with a 100% survival for 2 h after treatment. The effects are associated with the rise in the circulating blood volume and CI, and the decrease in TPRI, with the increase in RBF and HBF, and persistently lowered MBF. Both splenectomy and ligation of the suprahepatic veins inhibit histamine-induced increase in circulating blood volume as well as cardiac and regional haemodynamic effects. It can be concluded that histamine administered icv activates central endogenous compensatory mechanisms, which leads to the reversal of haemorrhagic shock conditions due to the mobilisation of blood from venous reservoirs, the increase in circulating blood volume and its redistribution. Moreover, histamine evokes the rises in Cl and perfusion of the renal and skeletal muscle vascular regions.     

Cardiovascular Effects of Methylmethacrylate Cement

Experiments were carried out on dogs in an attempt to identify the mechanisms underlying the systemic hypotension associated with the application of acrylic cement substances to raw bone surfaces, as in reconstructive hip surgery. Intravenous injection of the liquid component of such cements (monomeric methylmethacrylate) into six dogs produced a significant fall in blood pressure together with an increase in heart rate and cardiac output. This seemed to be due to peripheral vasodilatation caused directly by the monomer and not through the release of histamine. Absorption of free monomer from the mixed cement into the systemic circulation at operation is likely to have the same effect. Precautionary measures can be taken and groups of patients who are especially at risk can be identified, thus reducing the hazards of total hip replacement.     

Effects of L-leucine methyl ester (Leu-OMe) on mouse peritoneal mast cells: characterization of histamine release versus cytotoxicity.

L-Leucine methyl ester (Leu-OMe), a lysosomotropic compound, has been found to eliminate several lysosome-rich cellular subtypes and all natural killer cell function from peripheral blood mononuclear cells. In this report, the effect of Leu-OMe on mouse peritoneal mast cells is described. The L-Leu-OMe induced the release of histamine from mouse peritoneal mast cells in a dose-dependent manner (0.25 to 3 mM), while its D-stereoisomer had no effect. L-Leu-OMe displayed also a potent histamine release effect on purified mast cells, indicating a direct effect on mast cells. The monitoring of radioactive chromium release versus histamine release showed that both processes may be unrelated for Leu-OMe concentrations inferior to 1.5 mM. At higher doses, L-Leu-OMe, but not its D-stereoisomer, exerted a potent cytotoxic effect on mast cells. The secretory effect of Leu-OMe was temperature- and energy-dependent. Experiments performed in the absence of extracellular calcium and magnesium demonstrated that these divalent cations were not necessary for the Leu-OMe-induced histamine release, and their deprivation even involved a higher histamine release. The secretory characteristics of the Leu-OMe-induced histamine release appeared to be different from those of the IgE-induced ones. These results support the conclusion that exposure of mouse peritoneal mast cells to high doses of L-Leu-OMe results in killing of these cells, that are new targets of this lysosomotropic agent.     

Pathogenesis of Lethal Shock After Intravenous Staphylococcal Enterotoxin B in Monkeys

The pathogenesis of shock in the rhesus monkey given intravenous staphylococcal enterotoxin B (SEB) is not understood. Several cardiovascular changes produced by a highly purified preparation of SEB were studied after administration of doses ranging from 50 to 1,000 mug/kg. Irreversible arterial hypotension was found consistently at the higher doses. Arterial blood pressure and cardiac output declined substantially as shock developed. Total peripheral vascular resistance did not rise at any time, but showed a significant fall during the late stages of shock. Portal and central venous pressures remained essentially unchanged. Venous O(2) content and pO(2) declined gradually throughout the period of toxemia, but arterial O(2) content remained constant until just prior to death, when a slight fall was noted in some monkeys. These changes were consistent with a pooling of blood in the peripheral vascular beds and seemed to resemble cardiovascular responses reported to occur in monkeys during shock due to bacterial endotoxin. Epinephrine, administered in the late stages of shock, caused arterial pressure to increase almost immediately and cardiac output to return to normal about 1 min later. Although life could occasionally be prolonged for several hours by continuous or intermittent epinephrine infusions, this therapy never succeeded in reversing the lethal effects of high doses of SEB.     

Treatment of the inadequate endometrium in infertility

The one feature that characterizes all shock, regardless of its cause, is a reduction in the effective circulating blood volume. The reduced blood volume leads to decreased venous return, decreased cardiac output, vasoconstriction, tachycardia, hypotension, tissue anoxia and death if the sequence of events is uninterrupted. Immediate therapy must be directed at restoration of the blood volume, preferably with whole blood. Infection must be controlled by use of antibiotics intramuscularly and intravenously. If shock persists, aqueous adrenal extract should be administered in large quantities. As a last resort, a vasopressor should be tried.