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Background and objective: Tissue depletion of adenosine during endotoxaemia has previously been described in the lung. Therapeutic approaches to prevent adenosine depletion and the role of A1 and A2 receptor agonists, however, have not been investigated until now. Methods: In isolated and ventilated rabbit lungs, it was tested whether pretreatment with adenosine A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA; 10-7 mol, n = 6) or A2 receptor agonist 5′-(N-cyclopropyl)-carboxyamido adenosine (CPCA; -7 mol, n = 6) prior to injection of lipopolysaccharide (LPS) (500 pg mL 1) influenced pulmonary artery pressure (PAP), pulmonary energy content and oedema formation as compared with controls, solely infused with LPS (n = 6). Release rates of adenosine and uric acid were determined by high-performance liquid chromatography. Pulmonary tissue concentrations of high-energy phosphates were measured and the adenine nucleotide pool, adenosine 5′-triphosphate (ATP)/adenosine 5′-diphosphate (ADP) ratio and adenylate energy charge of the pulmonary tissue were calculated. Results: Administration of LPS induced increases in PAP within 2 h up to 20.8 ± 2.9 mmHg (P <0.01). While pretreatment with the A1 agonist merely decelerated pressure increase (13.8 ± 1.1 mmHg, P <0.05), the A2 agonist completely suppressed the pulmonary pressure reaction (9.6 ± 1.0mmHg, P<0.01). Emergence of lung oedema after exclusive injection of LPS up to 12.0 ± 2.9g was absent after A1 (0.6 ± 0.5 g) and A2 (-0.3 ± 0.2 g) agonists. These observations were paralleled by increased adenosine release rates compared with LPS controls (P < 0.05). Moreover, tissue concentrations of ADP, ATP, guanosine 5′-diphosphate, guanosine 5′-triphosphate, nicotinamide-adenine-dinucleotide and creatine phosphate were significantly reduced after LPS. Consequently, the calculated tissue adenine nucleotide pool and the adenylate energy charge increased after adenosine receptor stimulation (P = 0.001). Conclusions: Adenosine A1- and A2-receptor agonists reduced LPS-induced vasoconstriction and oedema formation by maintenance of tissue energy content. Thus, adenosine receptor stimulation, in particular of the A2 receptor, might be beneficial during acute lung injury. [ABSTRACT FROM AUTHOR]

Background and objective: An anti-inflammatory effect of α2-adrenoreceptor agonists has been suggested. Phospholipase A2 is a key enzyme in the production of precursors of inflammatory lipid mediators. The aim of the present study was to investigate the effect of clonidine on phospholipase A2 activity in an established in vitro model. Methods: Human being platelet membranes containing active phospholipase A2 were exposed to buffer control or to three increasing concentrations of clonidine. Phospholipase A2 was measured by a radioisotope technique. Results: A massive increase in phospholipase A2 activity was measured after clonidine exposure leading to final values of 92.5 ± 3.1 pmol mg protein-1 min-1 (4.5-fold higher than control values; P ⩽ 0.01 vs. control). After clonidine exposure the maximal reaction velocity increased, while the Michaelis-Menten constant did not change. The Lineweaver-Burk representation suggested an interaction of clonidine with the phospholipase A2-substrate complex as well as the phospholipase A2 molecule. Conclusion: We conclude that the putative anti-inflammatory effect of clonidine was not caused by inhibition of phospholipase A2. [ABSTRACT FROM AUTHOR]

During the past few decades, intensive collaborative research in the fields of chronic and acute inflammatory disorders has resulted in a better understanding of the pathophysiology and diagnosis of these diseases. Modern therapeutic approaches are still not satisfactory and shock, sepsis and multiple organ failure remain the great challenge in intensive care medicine. However, the treatment of inflammatory diseases like rheumatoid arthritis, ulcerative colitis or psoriasis also represents an unresolved problem. Many factors contribute to the complex course of inflammatory reactions. Microbiological, immunological and toxic agents can initiate the inflammatory response by activating a variety of humoral and cellular mediators. In the early phase of inflammation, excessive amounts of interleukins and lipid-mediators are released and play a crucial role in the pathogenesis of organ dysfunction. Arachidonic acid (AA), the mother substance of the pro-inflammatory eicosanoids, is released from membrane phospholipids in the course of inflammatory activation and is metabolised to prostaglandins and leukotrienes. Various strategies have been evaluated to control the excessive production of lipid mediators on different levels of biochemical pathways, such as inhibition of phospholipase A, the trigger enzyme for release of AA, blockade of cyclooxygenase and lipoxygenase pathways and the development of receptor antagonists against platelet activating factor and leukotrienes. Some of these agents exert protective effects in different inflammatory disorders such as septic organ failure, rheumatoid arthritis or asthma, whereas others fail to do so. Encouraging results have been obtained by dietary supplementation with long chain w-3 fatty acids like eicosapentaenoic acid (EPA). In states of inflammation, EPA is released to compete with AA for enzymatic metabolism inducing the production of less inflammatory and chemotactic derivatives. [ABSTRACT FROM AUTHOR]

This single-center study prospectively assessed the microbial contamination of anesthetic syringes handled perioperatively under different conditions. We documented high rates of bacterial contamination, with strong but statistically nonsignificant differences between handling groups. Our results identify skin contact as the main source of contamination, and thus we emphasize the impact of proper hand hygiene., (Copyright © 2016 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Endothelin-1 (ET-1) is a mediator of lung diseases and a potent pulmonary vasoconstrictor. In addition to thromboxane A2, it participates in the formation of lung edema. Both lidocaine and mepivacaine attenuate the increase of pulmonary arterial pressure (PAP) and lung edema development. We examined the effects of procaine, bupivacaine, and ropivacaine on experimentally evoked PAP increase and ET-1 release., Methods: PAP and lung weight were measured in isolated rat lungs during perfusion with Krebs-Henseleit hydroxyethyl starch buffer. Bupivacaine, ropivacaine, or procaine was added to the solution at concentrations of 10(-2)-10(-7) mg/kg. ET-1 levels were measured in the perfusate by enzyme-immunoassay, and thromboxane A2 levels were assayed by radioimmunoassay. N-formyl-L-leucine-methionyl-L-phenylalanine was used to activate human polymorphonuclear neutrophils., Results: Bupivacaine, ropivacaine, and procaine significantly attenuated increases of PAP (P < 0.05) and resulted in a reduction of lung weight in these treatment groups compared with the sham group (P < 0.05). The long-acting anesthetics bupivacaine and ropivacaine (P < 0.05), but not procaine, reduced ET-1 levels, produced low inflammation rates, and did not affect lung structures at doses from 10(-3) to 10(-6) mg/kg., Conclusion: Bupivacaine and ropivacaine attenuated N-formyl-L-leucine-methionyl-L-phenylalanine-induced PAP, reduced lung edema, and diminished ET-1 release. Lidocaine and mepivacaine are more effective in reducing PAP and edema formation, but long-acting local anesthetics also inhibit ET-1 depletion and therefore have increased anti-inflammatory properties.

The endothelin/endothelin-receptor system is a key player in the regulation of vascular tone in mammals. We raised and characterized an antiserum against rat ETB receptor and investigated the distribution of ETB receptors in different vascular beds during postnatal development (day 0 through day 28) and in the adult rat. We report the tissue-specific and age-dependent presence of vasoconstrictor ETB receptors. At the time of birth, vascular smooth muscle cells from all tissues examined did not exhibit ETB receptor immunoreactivity. The occurrence of ETB receptor immunoreactivity in the postnatal development was time dependent and started in small coronary and meningeal arteries at day 5, followed by small mesenteric arteries as well as brachial artery and vein at day 14. At day 21, ETB receptors were present in the media of muscular segments of pulmonary artery, large coronary arteries, and intracerebral arterioles. At day 28, ETB receptor immunoreactivity was evident in interlobular renal arteries, vas afferens, and efferens. Large renal arteries, mesenteric artery, and elastic segments of pulmonary arteries, as well as coronary and mesenteric veins, did not exhibit ETB receptor immunoreactivity. These data demonstrate the age-dependent and tissue-specific presence of ETB receptors, mainly on arterial smooth muscle cells in the vascular system of the rat.

In the heart, the endothelin (ET)/endothelin-receptor system is markedly involved in pathophysiological mechanisms underlying various cardiac diseases. Based upon pharmacological studies both ET-receptor subtypes take part in the regulation of coronary vascular tone, however, their detailed cellular distribution in the coronary vascular bed based upon direct mRNA and protein detection is unknown. This issue was addressed in the rat heart by means of non-radioactive in situ hybridization, RT-PCR, and immunohistochemistry. Expression of vascular ET(A)-receptors was detected in arterial smooth muscle and capillary endothelium while ET(B)-receptors were present in arterial, venous, and capillary endothelium, and in arterial and venous smooth muscle cells. This differential distribution of the ET-receptor subtypes supports the concept that ET(A)- as well as ET(B)-receptors mediate arterial vasoconstriction, while postcapillary vascular resistance is exclusively regulated by ET(B)-receptors. The observed capillary endothelial expression of the ET(A)-receptor correlates with the known ability of ET(A)-receptor antagonists to attenuate increases in cardiac microvascular permeability during endotoxin shock and ischemia/reperfusion injury.

Heme oxygenase (HO) plays a pivotal role for the maintenance of liver blood flow and hepatocellular integrity after hemorrhagic shock. We investigated the role of Kupffer cells and neutrophils as paracrine modulators of hepatocellular HO-1 gene expression in a rat model of hemorrhage and resuscitation. Male Sprague-Dawley rats (n = 6-10/group) were anesthetized (pentobarbital, 50 mg/kg intraperitonal) and subjected to hemorrhagic shock (mean arterial blood pressure: 35 mmHg for 60 min) or a sham protocol. Based on the time course of HO-1 gene expression, the effect of various antioxidants, Kupffer cell blockade [gadolinium chloride (GdCl3); 10 mg/kg; 24 h prior to hemorrhage or dichloromethylene diphosphonate (Cl2MDP); 1 mg/kg; 2 days prior to hemorrhage], or neutrophil depletion (vinblastine, 0.5 mg/kg, 5 days prior to hemorrhage) on induction of the HO-1 gene was assessed at 5 h of resuscitation, i.e., the time point of maximal induction. Kupffer cell blockade and antioxidants abolished HO-1 mRNA and protein induction after hemorrhage, while neutrophil depletion failed to affect hepatocellular HO-1 gene expression. In addition, Kupffer cell blockade aggravated hepatocellular injury. N-formyl-methionine-leucyl-phenylalanin (fMLP) induced a substantial influx of neutrophils into the liver but failed to induce hepatocellular HO-1 mRNA expression. These data suggest that Kupffer cells but not neutrophils induce an adaptive hepatocellular stress response after hemorrhage and resuscitation. Oxygen-free radicals released by Kupffer cells may serve as paracrine regulators of a hepatocellular stress gene which is necessary to maintain liver blood flow and integrity under stress conditions.

Endothelin-1 is the most potent vasoconstrictor known to date. This peptide is believed to play a pathophysiological role in the development of vasospasm, the most important complication of subarachnoid hemorrhage (SAH). In the present study we investigated the release of endothelin-1 in SAH and analyzed the cellular source of this peptide. At a protein and mRNA level we were able to show that endothelin-1 is produced by mononuclear leukocytes. Complementary in vitro studies revealed that aging and subsequent hemolysis of blood is sufficient to induce production of endothelin-1 by mononuclear leukocytes. Thus, cerebrospinal fluid-derived mononuclear leukocytes are a source of endothelin-1 in patients suffering from SAH. This finding may have important therapeutic implications as anti-leukocyte strategies could prevent cerebrovascular complications in SAH patients.

Background and Objectives: Learning curves for anesthesia procedures in adult patients have been determined, but no data are available on procedures in pediatric anesthesia. The aim of this study was to assess the number of caudal blocks needed to guarantee a high success rate in performing caudal epidural analgesia in children., Methods: At a teaching hospital, the technical skills of 7 residents in anesthesiology who performed caudal blocks were evaluated during 4 months using a standardized self-evaluation questionnaire. At the start of the study period, the residents had no prior experience in pediatric anesthesia or in performing caudal epidural blocks. All residents entered the pediatric rotation after a minimum of 1 year of training in adult general and regional anesthesia. The blocks were rated using a binary score. For comparison, the success rates of 8 experienced staff anesthesiologists were collected during the same period using the same self-evaluation questionnaire. Statistical analyses were performed by generating individual and institutional learning curves using the pooled data. The learning curves were calculated with the aid of a least-square fit model and 95% confidence intervals were estimated by a Monte Carlo procedure with a bootstrap technique., Results: The success rate of residents was 80% after 32 procedures (95% confidence interval of 0.59 to 1.00). The pooled success rate of the staff anesthesiologists was 0.73 (mean) with a standard deviation of 0.45, which was not statistically different from the success rate of the residents., Conclusion: High success rates in performing caudal anesthesia in pediatric patients can be acquired after a limited number of cases. Success rates of residents learning this procedure are comparable to the results of staff anesthesiologists.

Unlabelled: Hydroxyethyl starch (HES) solutions are widely used to replace intravascular volume. HES solutions differ from each other with regard to molecular weight and mode of hydroxyl substitution (degree of hydroxylation, C2:C6 hydroxyethyl ratio, concentration), factors which may have varying effects on coagulation. We studied, in vitro, three different HES preparations (molecular weight/degree of hydroxylation/concentration/C2:C6 ratio of substitution 70.000/0. 5/6%/3.2; Pharmacia & Upjohn Co., Erlangen, Germany; 130.000/0. 4/6%/11.2 and 200.000/0.5/6%/4.6; Fresenius Co., Bad Homburg, Germany) and, for comparison, lactated Ringer's solution (RL) at 33% and 66% dilution with whole blood. The influence of hemodilution was measured by using routine laboratory variables and SONOCLOT (Sonoclot II Coagulation and Platelet Function Analyzer, Sienco Co.) analysis, using a viscoelastic test, on the cellular as well as on the plasmatic hemostatic system. For statistical analysis of quantitative data, we used nonparametric analysis of variance and adequate post hoc tests. Qualitative data were analyzed by using the nonparametric Kruskal-Wallis test. A P value below 0.05 was considered significant. In contrast to the control group with RL, the liquid phase of coagulation (activated clotting time) was slightly affected by the 33% diluted HES solutions. HES 70.000, 130. 000, and 200.000 interfered significantly with the early stage of coagulation as expressed by the clot rate (gel/fibrin formation). Clot maturation and speed of maturation (time to peak) were strongly affected by HES 70.000 at all grades of dilution. HES 130.000 showed a faster clot formation process compared with the other HES solutions. HES 130.000 diluted 33% showed a better clot retraction as compared with the other HES solutions. In conclusion, in vitro hemodilution comparing different medium molecular weight HES solutions reveals that HES 130.000 seems preferable regarding some aspects of clot formation and retraction. RL affected clot formation only minimally, except for the early activation of clotting, which was measured by a shortened activated clotting time., Implications: We investigated the effect of different hydroxyethyl starch (HES) solutions (70.000, 130.000, 200.000) on coagulation. Regarding clot formation and retraction, HES 130.000 had some advantages over the other tested HES solutions. Lactated Ringer's solution affected coagulation only minimally, except for the early stage of clot formation.

Endothelin-1 (ET-1) has been reported to induce pulmonary vasoconstriction via either ET(A) or ET(B) receptors, and vasorelaxation after ET-1 injection has been observed. Our study investigated the effects of ET-1 in isolated rabbit lungs, which were studied at basal tone (part I) and after preconstriction (U-46619; part II). Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. In part I, ET-1 (10(-8) M; n = 6; control) was injected after pretreatment with the ET(A)-receptor antagonist BQ-123 (10(-6) M; n = 6) or the ET(B)-receptor antagonist BQ-788 (10(-6) M; n = 6). The same protocol was carried out in part II after elevation of pulmonary vascular tone. ET-1 induced an immediate PAP increase (DeltaPAP 4.3 +/- 0.4 mmHg at 10 min) that was attenuated by pretreatment with BQ-123 (P < 0.05 at 10 min and P < 0.01 thereafter) and that was more pronounced after BQ-788 (P < 0.01 at 10 min and P < 0.001 thereafter). In part II, ET-1 induced an immediate rise in PAP with a maximum after 5 min (DeltaPAP 6.3 +/- 1.4 mmHg), leveling off at DeltaPAP 3.2 +/- 0.2 mmHg after 15 min. Pretreatment with BQ-123 failed to attenuate the increase. BQ-788 significantly reduced the peak pressure at 5 min (0.75 +/- 0.4 mmHg; P < 0.001) as well as the plateau pressure thereafter (P < 0.01). We conclude that ET-1 administration causes pulmonary vasoconstriction independent of basal vascular tone, and, at normal vascular tone, the vasoconstriction seems to be mediated via ET(A) receptors. BQ-788 treatment resulted in even more pronounced vasoconstriction. After pulmonary preconstriction, ET(A) antagonism exerted no effects on PAP, whereas ET(B) antagonism blocked the PAP increase. Therefore, ET-1-induced pulmonary vasoconstriction is shifted from an ET(A)-related to an ET(B)-mediated mechanism after pulmonary vascular preconstriction.

Background: Severe pancreatitis is often complicated by shock and acute lung failure. Little is known about the pathophysiologic impact of the 16.6-kD lectine, named pancreatitis-associated protein (PAP), which is expressed during pancreatitis and which reduces mortality in a rat model with severe pancreatitis. Therefore, the aim of this study was to investigate the effects of PAP on the pulmonary vasculature after leukocyte activation with N-formyl-Met-Leu-Phe (fMLP)., Methods: The experiments were performed in buffer-perfused isolated rabbit lungs. Mean pulmonary artery pressure, weight gain, and thromboxane A2 synthesis of the lungs were monitored. PAP was obtained by affinity chromatography of pancreas juice from pancreatitic rats. The authors tested whether treatment with PAP (260 microg/l, n = 9; or 500 microg/l, n = 6) before fMLP injection (10(-6) M) influences mean pulmonary artery pressure and edema formation. Lungs that were treated only with fMLP (n = 6) served as controls. Additional experiments in which PAP was applied were performed to study whether PAP (260 microg/l, n = 3; 500 microg/l, n = 3; 1,000 microg/l, n = 3) itself effects lung vasculature., Results: Application of fMLP resulted in an increase of mean pulmonary artery pressure (+/- SD) from 8 +/- 2 mmHg up to 26 +/-13 mmHg (P < 0.01) at a flow of 150 ml/min. Pretreatment with PAP reduced the peak pressure developed after fMLP to 15 +/- 7 mmHg (PAP 260 microg/l; P < 0.05) and to 9 +/- 4 mmHg (PAP 500 microg/l), respectively. In addition, the fMLP-induced lung weight gain of 9 +/- 7 g in the controls was prevented by pretreatment with PAP after 150 min in either concentration. In parallel to the attenuated pressure increase, thromboxane A2 release was significantly suppressed in the 260-microg/l (200 +/- 220 pmol x ml(-1) x min(-1); P < 0.01) and 500-microg/l (285 +/- 70 pmol x m(-1) x min(-1); P < 0.05) PAP groups compared with controls (1,138 +/- 800 pmol x ml(-1) x mi(-1)). Treatment with PAP alone in either concentration did not induce any changes in mean pulmonary artery pressure, weight gain, or thromboxane A2 release., Conclusion: Clinically relevant concentrations of PAP prevented fMLP-induced vasoconstriction and edema formation in the lung. These findings point toward a protective effect of PAP on polymorphonuclear neutrophil leukocyte-mediated lung injury.

Unlabelled: The underlying mechanisms of hemoglobin (Hb)-induced vasoconstriction are not yet well understood. The aim of this study was to elucidate the influence of nitric oxide (NO) and endothelin (ET) on Hb-induced pulmonary vasoconstriction. Therefore, an autologous Hb preparation was administered into isolated rabbit lungs, in which pulmonary artery pressure (PAP) and weight gain was monitored. Either glyceroltrinitrate (GTN; 10(-5) M; n=6), L-arginine (10(-2) M; n=6), L-NAME (10(-4)M; n=6), ET(A)- or ET(B)-receptor antagonists (BQ,23, 10 6M, n=6) or (BQ788, 10(-6) M, n=6) were added to the perfusion fluid and NOx and thromboxane A2 levels were measured., Results: In the control group the Hb-stimulation resulted in a pressure response up to 25.1+/-2.1 mmHg (p < .05), which was 136+/-6% of the reference value. The PAP increase was significantly (p < .05) blunted after GTN (71+/-5%), L-arginine (93+/-6%) and BQ788 (88+/-7%). Pretreatment with L-NAME (139+/-13%) or BQ123 (115+/-9%) did not show significant changes in PAP., Conclusion: The reduction of the Hb-induced pulmonary hypertension by NO-donors points toward the inactivation of NO by free hemoglobin. Likewise, ET(B)-receptor mediated vasoconstrictive effects without changes in NOx concentrations seem to play a pathogenetic role in the Hb-induced pulmonary vasoconstriction.

Objective: To examine the pathophysiologic role of vasoactive eicosanoids and endothelin-1 in granulocyte-mediated effects in the pulmonary vasculature., Design: Prospective experimental study in rabbits., Setting: Experimental laboratory in a university teaching hospital., Subjects: Thirty adult rabbits., Interventions: The experiments were performed on 30 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution., Measurements and Main Results: The pulmonary arterial pressure and the lung weight gain were continuously registered. Intermittently perfused samples were taken to determine endothelin-1 and thromboxane A2 concentrations. Six experiments without intervention served as the sham group. The granulocytes in the pulmonary circulation were stimulated with N-formyl-L-leucin-methionyl-L-phenylalanine (FMLP; 10(-6) M; control, n = 6). To investigate whether activated granulocytes influence the pulmonary vasculature via endothelin-1, the endothelin-A receptor antagonist LU135252 (10(-6) M) was added to the perfusate before FMLP injection (n = 6). The potential involvement of thromboxane A2 in granulocyte-endothelial interaction was investigated by pretreatment with the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). Activation of granulocytes resulted in an acute increase in pulmonary arterial pressure (>9 mm Hg), which was followed by a second delayed pressure increase after 60 mins (>14 mm Hg) and was paralleled by a massive generation of thromboxane A2 (>250 pg/ mL). Fifteen minutes after FMLP-injection, endothelin-1 was detectable in the perfusate. Pretreatment with the selective endothelin-A antagonist LU135252 significantly (p< .01) reduced the initial pressure response after FMLP stimulation, while diclofenac significantly reduced (p < .05) the delayed pressure increase. Using diclofenac (10 microg/mL) in conjunction with LU135252 (10(-6) M; n = 6) before FMLP injection significantly reduced the early and the delayed pressure increase., Conclusions: Activated granulocytes seem to enhance pulmonary vascular resistance via endothelin-1 and thromboxane A2. The endothelin-1 effects are probably mediated via endothelin-A receptors since the endothelin-A receptor antagonist LU135252 was able to suppress the early pressure reaction after FMLP injection, whereas the cyclooxygenase inhibitor diclofenac was able to reduce the second pressure increase.

Purpose: The interaction of activated granulocytes and endothelial cells influences not only capillary permeability but also increases pulmonary vascular resistance. The aim of this study was to evaluate the role of endothelin-1 (ET-1) during the granulocyte-mediated increase in pulmonary pressure., Methods: The experiments were performed on isolated and ventilated rabbit lungs perfused with a blood-free buffer solution. Isolated, washed human granulocytes were injected into the pulmonary artery and stimulated by 10(-6) M N-formyl-L-leucin-methionyl-L-phenylalanine (FMLP). Pulmonary arterial pressure (PAP) was continuously registered, and perfusate samples were taken to determine ET-1 and eicosanoid levels. To analyse the role of ET-1, six lung preparations were pretreated with the ETA receptor antagonist BQ123 (10(-6) M) prior to FMLP injection. To analyse the role of thromboxane A2, six additional lung preparations were pretreated with the cyclooxygenase inhibitor diclofenac (10 micrograms/ml). Additionally, granulocytes were stimulated in vitro with FMLP for 15 min, and ET-1 concentration was measured in the supernatant., Results: Immediately after FMLP injection, PAP increased to 18.5 +/- 1.6 mmHg, descending to values 4.8 +/- 0.8 mmHg above the baseline after 15 min. At this time, ET-1 could be detected in the perfusate. The concentrations of the cyclooxygenase products thromboxane A2 and prostacyclin remained nearly unchanged during the observation period. Pretreatment with the ETA receptor antagonist BQ123 significantly reduced the pressure response after FMLP injection (p < 0.01 at 5 and 10 min; p < 0.05 at 15 and 30 min). Pretreatment with the cycloocygenase inhibitor diclofenac failed to inhibit the pressure reaction evoked by activated granulocytes. In contrast to this, ET-1 was not detected after in vitro stimulation of granulocytes., Conclusion: ET-1 is involved as a mediator of pulmonary vasoconstriction due to granulocyte activation. Since in vitro FMLP-stimulation of human granulocytes did not induce ET-1 production, it seems likely that isolated activated granulocytes would not produce ET-1, but provoke the endothelial cells to release ET-1 in the pulmonary circulation.

The endothelins (ETs) are a family of three vasoactive peptides (ET-1, ET-2, ET-3) that were first described in 1988. ETs have a wide range of action including vasoconstriction, vasodilatation, bronchoconstriction, and mitogenesis. Two types of ET receptors, classified as ETA and ETB receptors, have been identified in gene technology. Endothelins are produced by endothelial cells, smooth muscle cells, and bronchial epithelial cells. Their vasoactive effects contribute not only to homoeostasis but ETs seem also to be involved in several pulmonary diseases. Elevated ET plasma levels have been found in patients suffering from asthma, pulmonary fibrosis, pulmonary hypertension, and acute lung injury. This review gives a short summary of the actual facts in endothelin research, focussing on the effects of ET-1 in pulmonary circulation.