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PubMed2002

[Physiological analysis of plasma hypo-osmolality in pneumonia].

AIM: To study the physiological mechanisms of plasma hypoosmolality in patients with pneumonia and on this basis to elaborate principles of therapy for this condition. MATERIALS AND METHODS: 52 individuals of different age, including 26 patients with pneumonia, were examined. Osmolality, the concentrations of ions of sodium, potassium, magnesium, and creatinine were measured in the serum. RESULTS: The patients with pneumonia were found to have osmolality, hyponatremia in combination with severe hypodiuresis, high urinary osmotic pressure and intensive reabsorption of osmotically free water in the kidney, which leads to blood dilution. As hypoosmolality usually causes higher diuresis and decreased urinary osmolality; hypodiuresis with high urinary osmolality in pneumonia is indicative of effective renal performance and its altered regulation evidently due to the hypersecretion of vasopressin or to the decreased formation of a number of autacoids in the kidney. CONCLUSION: Blood hypoosmolality and hyponatremia in the examined patients result from inadequate blood osmolality and high urinary osmotic concentrating. The principles of this condition in pneumonia are discussed and aquaretics are proposed for use as pathogenetic therapy.

Acute Disease↗
PubMedDate not supplied

[Participation of nitric oxide and arachidonic acid metabolites via cytochrome - P450 in the regulation of arterial blood pressure].

Nitric oxide and cytochrome P450 arachidonic acid metabolites participate in blood pressure regulation. The synthesis of these autacoids leads to arterial hypertension. However, it is not known whether there is an interaction between them. Therefore, we studied the modulatory effect of nitric oxide and cytochrome P450-arachidonic acid metabolites, their interaction on blood pressure, and the renal content of cytochrome P450. Male Wistar rats were divided: 1) control, 2) L-NAME (100 mg/kg/d p.o.), 3) L-NAME + SnCl2 (10 mg/kg/d i.p.), and 4) L-NAME + dexamethasone (1 mg/kg/d s.c.). We measured blood pressure and collected urine and blood for nitric oxide measurement. NO2 was quantified by HPLC. Blood pressure was: control, 97 +/- 7 mmHg; L-NAME, 151 +/- 4.6 mmHg; L-NAME + SnCl2, 133 +/- 3 mmHg, and L-NAME + dexamethasone 152 +/- 4.5 mmHg. Urine nitrite concentration was: 1) 1.832 +/- 0.32, 2) 1.031 +/- 0.23, 3) 1.616 +/- 0.33, and 4) 1.244 +/- 0.33 mumol/mL, while the concentration in blood was: 1) 0.293 +/- 0.06, 2) 0.150 +/- 0.05, 3) 0.373 +/- 0.13, and 4) 0.373 +/- 0.07 mumol/mL. L-NAME + SnCl2 decreased cytochrome P450 renal content, and L-NAME + dexamethasone showed a similar response. In conclusion, both, nitric oxide and CYP-arachidonic acid metabolites play a role in the regulation of blood pressure. Nitric oxide also partially regulates renal cytochrome P450 content.

Animals↗
PubMed2000

Bradykinin B2 receptor as a potential therapeutic target.

Kinins are peptide hormones that exert pathophysiological as well as pronounced beneficial physiological effects, mainly by stimulation of bradykinin (BK) B(2) receptors. Owing to the strong proinflammatory properties of kinins resulting from vasodilation, plasma extravasation, activation of mast cells, fibroblasts and macrophages, stimulation of sensory neurons, and the release of nitric oxide, prostaglandins, leukotrienes and cytokines, kinins are believed to play an important role in a variety of inflammatory diseases and pain. Beneficial effects of BK B(2) receptor antagonists in perennial rhinitis, asthma and brain edema have already been shown in clinical trials. Recently, the potential therapeutic utility of BK B(2) receptor antagonists has been extended by the discovery of orally active, nonpeptide BK B(2) receptor antagonists and the identification of novel indications for their use. On the other hand, kinins also have been identified as potent antihypertensive and organ-protective peptides. They have been shown to have vasodilatory, antihypertrophic, antiaggregatory and fibrinolytic effects due to the BK B(2) receptor-mediated release of the autacoids nitric oxide, prostacyclin and tissue plasminogen activator. A recent finding is that kinins are also involved in ischemic preconditioning. Orally active, nonpeptide BK B(2) receptor agonists as potential novel therapeutic agents in cardiovascular medicine have also been identified. In conclusion, interaction with the BK B(2) receptor by either its blockade or its stimulation offers promising therapeutic approaches. BK B(2) receptor antagonists may prove to be useful in the treatment of asthma, rhinitis, arthritis, colitis, pancreatitis, sepsis, edema, tissue injury, pain and possibly infections, hepatorenal syndrome, Alzheimer's disease and lung cancer. BK B(2) receptor agonists have potential in the treatment of cardiovascular diseases like hypertension, cardiac hypertrophy, restenosis and myocardial infarction and diabetic disorders.

Journal Article↗
PubMed1992

Receptor-mediated internalization of bradykinin. DDT1 MF-2 smooth muscle cells process internalized bradykinin via multiple degradative pathways.

This study was undertaken to evaluate the role of internalization in the action of the peptide autacoid bradykinin (BK). At 4 degrees C [3H]BK binds to an apparently single class of B2 kinin receptors on DDT1 MF-2 smooth muscle cells (C. M. Munoz, S. Cotecchia, and L. M. F. Leeb-Lundberg, manuscript submitted). At this temperature the [3H]BK binding was confined exclusively to the cell surface. On the other hand, at 37 degrees C the B2 receptor-specific cell surface [3H]BK binding was rapidly followed by a receptor-specific internalization of [3H]BK (t1/2 approximately 9 min). The internalization reached a steady-state level after 30-40 min that was 80-100% of the level of specifically bound [3H]BK on the cell surface at 4 degrees C, and this level was maintained for greater than or equal to 2 h. Internalized [3H]BK was routed via at least two intracellular degradative pathways which were distinguished primarily based on subcellular localization but also on a small but significant difference in the rate of [3H]BK degradation. One pathway was localized in a plasma membrane-enriched fraction and had a relatively high degradative capacity. Another pathway was localized in a microsomal fraction and had a relatively low degradative capacity. The internalized [3H]BK activity was rapidly released into the media (t1/2 approximately 24 min). Following a single round of internalization, the released activity consisted almost exclusively of small [3H]BK fragments (less than [3H]BK(1-5)). In contrast, at steady-state [3H]BK represented 30-40% of the released activity. While chloroquine (100 microM) did not alter the rate of [3H]BK internalization or release or the intracellular distribution of [3H]BK, this agent significantly decreased the rate of [3H]BK degradation in both pathways. In all, these results show that B2 kinin receptor-mediated internalization of BK is a process integral to the interaction of BK with DDT1 MF-2 smooth muscle cells and may be a mechanism for terminating BK actions by rapidly removing extracellular free and receptor-bound BK and accessing various intracellular BK degradative pathways.

Amino Acid Sequence↗
PubMed1992

Combined acute hypoxemia and hypercapnic acidosis increases atrial natriuretic polypeptide in conscious dogs.

To evaluate the changes in atrial natriuretic polypeptide during acute hypoxemia and acute hypercapnic acidosis, conscious mongrel dogs with controlled sodium intake were evaluated in four protocols: (1) 80 min of acute hypoxemia (PaO2 = 34 +/- 1 mm Hg) followed by 40 min of combined hypoxemia and hypercapnic acidosis (PaO2 = 38 +/- 1 mm Hg, PaCO2 = 60 +/- 3 mm Hg, pH = 7.15 +/- 0.03) (n = 7); (2) 40 min of combined acute hypoxemia and hypercapnic acidosis (PaO2 = 36 +/- 1 mm Hg, PaCO2 = 56 +/- 2 mm Hg, pH = 7.20 +/- 0.03) induced immediately following control measurements (n = 5); (3) 120 min of acute hypercapnic acidosis (PaCO2 = 58 +/- 1 mm Hg, pH = 7.20 +/- 0.01) (n = 5), and (4) 120 min of normoxemia and normocapnia (n = 7). These studies did not observe any association between urinary sodium excretion and circulating atrial natriuretic polypeptide during acute blood gas derangements in conscious dogs. The natriuresis with acute hypoxemia or acute hypercapnic acidosis was unaccompanied by change in plasma atrial natriuretic polypeptide concentrations. Conversely, the rise in circulating atrial natriuretic polypeptide during combined acute hypoxemia and hypercapnic acidosis was not associated with an increase in urinary sodium excretion. These observations do not exclude a role for atrial natriuretic polypeptide in altering sodium excretion during acute blood gas derangements, since the effects of this autacoid on renal sodium excretion may have been offset by other counterregulatory mechanisms of sodium excretion activated during the acute blood gas derangement.

Acidosis↗
PubMed2003

Modulation of cardiac remodeling by adenosine: in vitro and in vivo effects.

The increasing incidence of congestive heart failure has stimulated efforts to develop pharmacologic strategies to prevent or reverse the associated process of adverse cardiac remodeling. The possibility of utilizing endogenously generated factors that are capable of inhibiting this process is beginning to be explored. Adenosine, has been described as a retaliatory autacoid with homeostatic activities in the regulation of myocardial blood flow, catecholamine release, and reduction of injury resulting from periods of ischemia. Adenosine exerts a variety of actions that are consistent with the concept that it can reduce or inhibit the process of cardiac remodeling. In this manuscript, the basics of adenosine metabolism, its cell surface receptors and beneficial actions on the cardiovascular system are reviewed. In addition new, in vitro and in vivo data will be presented supporting the concept that adenosine exerts actions that may ameliorate adverse cardiac remodeling.

Adenosine↗
PubMed1992

Vasoconstrictor and vasodilator effects of serotonin in the isolated rabbit kidney.

The renal vascular effects of serotonin (5-HT) in vivo vary among preparations, which may reflect that this autacoid can modulate the vascular response to certain spasmogens. We investigated this phenomenon in the isolated rabbit kidney perfused under constant flow (5 ml/min) with Krebs-bicarbonate buffer. Dose-response experiments to 5-HT were conducted before and during an infusion of half-maximal effective doses of norepinephrine (NE), phenylephrine (PE) or endothelin-1 (ET-1). Each infusion was varied to raise the perfusion pressure (PP) from a baseline of 18-28 mm Hg to a level of 80-100 mm Hg. In the absence of infused NE, PE or ET-1, bolus injections of 5-HT had little or no effect. However, in the presence of NE, 5-HT injections of 20 pmol to 20 nmol caused a dose-dependent increase in PP; higher doses (0.4-4 mumol) of 5-HT caused a dose-dependent decrease in PP. Similar results with 5-HT were obtained in the presence of an infusion of PE. However, in the presence of ET-1, 5-HT injections elicited only a modest increase in PP, which was significantly less than the increase in the presence of NE; and they did not have the vasodilator effect on the isolated perfused kidney. Histamine injections only increased but did not decrease the PP in PE-precontracted renal vasculature. Infusion of 5-HT at 20 nmol/min potentiated the dose-dependent effect of NE on PP, but 5-HT infusion of 1 mumol/min attenuated the effect of NE on PP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Eicosanoid production by the human gastric cancer cell line AGS and its relation to cell growth.

Eicosanoids have the ability to stimulate or inhibit the proliferation of epithelial cells, and they have been shown to modulate the growth characteristics of certain tumor cell lines. In addition, many epithelial cells have the ability to produce eicosanoids, which may then serve as autocrine growth factors. We have measured the eicosanoids produced by the human stomach cell line AGS using reverse-phase high-performance liquid chromatography. AGS cells were incubated with [3H]arachidonic acid and stimulated to release eicosanoids by the calcium ionophore A23187. Unlike its counterpart from the normal stomach, the AGS tumor cell line produced prominent amounts of the leukotrienes D4, C4, and B4; 6-keto-prostaglandin F1 alpha; thromboxane B2; hydroxyeicosatetraenoic acids; and smaller amounts of other prostaglandins in response to A23187. Under basal condition (in the absence of calcium ionophore), hydroxyeicosatetraenoic acid was produced in greatest relative amount compared with the other eicosanoids. To elucidate the potential autacoid role of these agents, exogenous eicosanoids were added to AGS cells, and proliferation was measured. Prostaglandins D2 and E2 suppressed the growth of AGS cells in a dose-dependent manner. On the other hand, leukotrienes D4 and C4 had a dose-dependent proliferative effect on cell growth. The lipoxygenase inhibitor nordihydroguaiaretic acid (10(-6), 10(-5) M) and hydrocortisone (10(-5) M) had dose-dependent suppressive effects on growth, whereas indomethacin (10(-6) M and 10(-5) M) had no effect. These results suggest that AGS cells preferentially metabolize arachidonic acid through the 5-lipoxygenase pathway, which results in the production of growth-stimulatory autocoids. Agents that selectively block this arm of eicosanoid metabolism might be useful therapeutic agents in the treatment of certain gastrointestinal cancers.

Arachidonic Acid↗
PubMedDate not supplied

The accumulation of extracellular matrix in the kidney: consequences on cellular function.

The mechanisms involved in the progression of chronic renal disease (CRD) have not been completely clarified. A role for hyperfiltration and increased intraglomerular pressure was proposed about twenty years ago, and experimental and clinical evidence supports, at least partially, this hypothesis. Moreover, a lot of experimental data point to the importance of different autacoids, including prostanoids, endothelial vasoactive factors, reactive oxygen species, cytokines and growth factors, in the genesis of the changes that characterize CRD. However, alternative mechanisms of progression may be involved such as the presence of abnormal extracellular matrix (ECM) proteins in kidney structures. By modifying the phenotype of renal cells, they may constitute a key factor in disease progression. Experimental studies support this hypothesis. Human mesangial cells cultured on collagen I (COLI) synthesize increased amounts of TGFss1 compared with cells cultured on collagen IV (COLIV). As a consequence of this increased TGFBeta1 synthesis, they also produce more collagens and fibronectin. Human umbilical vein endothelial cells cultured on COLI show a different pattern of endothelial vasoactive factor synthesis, compared with those on COLIV: they synthesize more endothelin-1 and less nitric oxide. Integrins and integrin-linked kinase (ILK) play a significant role in the genesis of these changes. Although an extrapolation of these data to human diseases can not be performed, they point to alternative mechanisms of chronic renal damage progression or renal dysfunction in kidney diseases. They also point to potential therapeutic targets such as integrins and ILK.

Animals↗
PubMed2005

Systemic inflammatory response during cardiopulmonary bypass and strategies.

Organ dysfunction after cardiopulmonary bypass (CPB) still is a major problem in patients undergoing cardiovascular surgery. Studies have demonstrated that systemic inflammatory response (SIR) remains one of the major causes of CPB-associated organ injury. The mechanism of SIR during CPB includes the interaction of blood and artificial surface and endotoxemia. The interaction of blood and artificial surface is initiated by protein adsorption. As a result of series of chain reactions, the numerous powerful inflammatory mediators, including hormones and autacoids, are formed and released. Subsequently, the contact system, coagulation system, complement system, fibrinolysis system, and leukocytes, platelets, and endothelial cells, are all activated to participate in the interaction of blood and artificial materials. These activations of different systems and blood cells can interact and magnify each other. CPB-associated endotoxemia has been demonstrated to intensify and deteriorate SIR during CPB. SIR leads to organ injury. In clinical setting, the most common SIR-related organ damage is pulmonary dysfunction, which often is manifested by decreasing of lung compliance, rise in shunt fraction, work of breathing, and likelihood of atelectasis and pneumonia. Strategies to control CPB-related SIR have been developed, such as improvement of biocompatibility of artificial surface (new biomaterials), temporary inhibition of blood cells activation ("blood anesthesia") during CPB, and blockage of the bioactivities and effects of inflammatory mediators.

Cardiopulmonary Bypass↗
PubMed2005

The future of traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors in the treatment of inflammation and pain.

Prostanoids act leading roles in a myriad of physiologic and pathologic processes because these autacoids participate in the amplification of biological responses induced by innumerable stimuli. The formation of prostanoids is operated by two synthases named cyclooxygenase(COX)-1 and COX-2. Traditional nonsteroidal antiinflammatory drugs (tNSAIDs) and COX-2 inhibitors (coxibs) give rise to antipyretic, analgesic, and antiinflammatory actions, through their reversible clogging of the COX channel of COX-2 - apart from aspirin which modifies irreversibly the catalytic activity of COX-2. tNSAIDs and COX-2 inhibitors resulted clinically equivalent for the relief of acute pain and symptoms of arthropathies but they failed to modify disease progression. Clinical evidence of the possible contribution of COX-1 in inflammation and pain in some occasion - as suggested by experimental and pharmacology studies - is orphan because none efficacy trial with COX inhibitors was designed to establish it. COX-2 inhibitors were developed with the aim to reduce the incidence of serious gastrointestinal (GI) adverse effects associated with the administration of tNSAIDs ensued as a consequence of the inhibition of cytoprotective COX-1-derived prostanoids. However, the reduced incidence of serious GI adverse effects compared to tNSAIDs demonstrated for 2 COX-2 inhibitors (e.g. rofecoxib and lumiracoxib) has been countered by an increased incidence of myocardial infarction and stroke detected in 5 placebo controlled trials involving the COX-2 inhibitors celecoxib, rofecoxib and valdecoxib. The future of COX-2 inhibitors will be an example of personalised medicine as their use will be restricted to patients who do not respond to tNSAIDs or with increased risk of GI complications.

Animals↗
PubMed1991

Platelet-activating factor impairs mucociliary transport and increases plasma leukotriene B4 in man.

We assessed the effect of inhaled platelet-activating factor (PAF) on tracheobronchial clearance, pulmonary function and blood pressure in seven healthy volunteers. After inhalation of 500 micrograms of PAF, retention of radioaerosol in ciliated airways measured at 4 h was 80% higher than in the control recording, and the clearance was reduced by 33% (p less than 0.005). Acetylsalicylic acid (ASA) did not abolish the phenomenon. PAF also decreased forced expiratory volume in one second (FEV1) by 16% (p less than 0.01), which was markedly attenuated by acetylsalicylic acid. The decrease in blood pressure after PAF (p less than 0.01) was not influenced by acetylsalicylic acid. Plasma leukotriene B4 (LTB4) was increased at 20 min after PAF inhalation (without and with ASA: mean 240 and 299 pg.ml.1, respectively) as compared to the baseline (144 and 166 pg.ml.1) and the values at 60 min after the challenge (133 and 178 pg.ml.1; p less than 0.05 and p less than 0.01, respectively). Only three out of seven subjects showed a bronchial hyperresponsiveness to methacholine measured 24 h after PAF. The PAF-induced reduction of mucociliary transport seems to be independent of cyclo-oxygenase products of arachidonic acid metabolism. These autacoids are, however, believed to contribute to the acute bronchial obstruction after PAF inhalation. In addition, inhaled PAF causes a transient increase in plasma LTB4.

Administration, Inhalation↗
PubMed2006

Prostaglandin production by human osteoclasts in culture.

OBJECTIVE: Prostaglandins (PG) are important mediators of bone metabolism with direct and indirect effects on bone cells. They may have important effects on osteoclasts, but it is not known if these cells can synthesize PG. We used 2 experimental models in order (1) to determine the presence and functionality of cyclooxygenase (COX) and phospholipase A2 (PLA2) enzymes in human osteoclasts and (2) to study their role in cell metabolism. METHODS: Experiments were undertaken on authentic human osteoclasts extracted from human fetuses (fhOC) and on human osteoclast-like (hOCL) cells differentiated from peripheral blood mononuclear cells. The presence of COX proteins was determined by immunohistochemistry. COX and PLA2 enzymatic activity was evaluated at the single-cell level by fluorescence microscopy. An enriched population of hOCL cells was used to evaluate total PG production and the influence of COX activity on bone resorption. RESULTS: COX-1 was expressed in the cytoplasm and COX-2 was distributed mainly near the nuclear membrane of osteoclasts. These cells showed a high basal level of COX activity that could be inhibited by pretreatment with COX inhibitors. Cytosolic PLA2 was present in both models. Human osteoclasts actively produced PG, and the COX-1 pathway was implicated in the control of bone resorption. CONCLUSION: These results indicate that PG may be important autacoids for the control of osteoclast biology and that the COX-1 pathway is implicated in the inhibition of bone resorption.

Animals↗
PubMed1990

Histamine, 5-HT & hyaluronidase in the venom of the scorpion Lychas laevifrons (Pock).

Factors involved in the pathophysiological changes such as severe pain, burning sensation, redness, swelling and edema in case of the scorpion L. laevifrons were investigated. The presence of pain-producing autacoids histamine 2.1 +/- 0.18 micrograms/mg and 5-HT 0.23 +/- 0.1 micrograms/ml was confirmed by thin layer chromatography and bioassay. Histamine releasing substance was detected in vitro in the chopped guineapig lung. Venom also contained hyaluronidase 5 x 10(-4) N-acetyl-D-glucosamine released/h/mg, which facilitates spread of the toxic principles in the tissues. It is concluded that histamine, 5-HT, histamine-releasing factor and hyaluronidase are partly involved in the pathophysiological changes induced by the venom. It is suggested that mepyramine and cyproheptadine may prove useful in the management of scorpion envenomation.

Animals↗
PubMed1992

Release of newly synthesized platelet-activating factor (PAF) from human polymorphonuclear leukocytes under in vivo conditions. Contribution of PAF-releasing factor in serum.

The behavior of platelet-activating factor (PAF) produced in stimulated human polymorphonuclear leukocytes (PMN) was investigated in the presence of serum under conditions close to those existing in vivo. When the cells were stimulated in the presence of the serum obtained from a PAF acetylhydrolase (PAF-AH)-deficient Japanese subject, over 60% of synthesized PAF was detected in the extracellular medium by bioassay, scintillation proximity RIA and selected ion monitoring/gas chromatography/mass spectrography analysis. The release of PAF from PMN after stimulation with FMLP and A23187 was also observed in the presence of normal serum treated with acid to inactivate PAF-AH. The heterogeneity of the molecular species of extracellular PAF was similar to that of intracellular PAF produced in stimulated PMN in the presence of PAF-AH-deficient serum, ruling out the possibility that a specific molecular species of PAF was preferentially released from the cells in the presence of the serum. As these data suggested the occurrence of PAF-releasing factor(s) in the serum, an attempt was made to partially purify this factor from PAF-AH-deficient serum and acid-treated normal serum by ammonium sulfate fractionation and column chromatography with DEAE-Cellulofine and Sepharose CL-6B. The molecular mass of PAF-releasing factor revealed on a TSK gel G3000 SW HPLC column was 240 kDa, which was different from that of albumin. The binding assay, newly developed for this study, revealed that the PAF-binding activity of PAF-releasing factor is stronger than that of albumin, and that the PAF-releasing factor forms a complex with PAF at low concentration (10(-9) M). PAF bound to this factor was difficult to be hydrolyzed by serum PAF-AH. On the other hand, the PAF/PAF-releasing factor complex had aggregatory activity toward washed rabbit platelets. These observations suggest that certain protein(s) releases and carries the PAF newly synthesized by PMN in blood plasma/serum. Thus it appears that PAF functions as an autacoid in vivo, along with other mediators.

Calcimycin↗
PubMedDate not supplied

Ascites in liver diseases.

The clinical course of patients with cirrhosis of the liver is frequently complicated by progressive impairment of renal sodium handling leading to the formation of ascites. The occurrence of ascites is generally accompanied by the activation of several hormones and intrarenal autacoids and a complex derangement of systemic, portal and renal hemodynamics. The earliest "underfilling" theory of sodium retention proposes that ascites formation leads to hypovolemia and secondary sodium retention. According to the "overflow" theory, ascites formation is a secondary event with respect to sodium retention, which occurs as a primary phenomenon in the absence of hypovolemia. A third recently developed theory suggests that peripheral arteriolar vasodilation is the primary event of intravascular underfilling. The major documented site involved in arteriolar vasodilation is the splanchnic circulation. Occurrence of underfilling is not related to a reduction of plasma volume but to the enlargement of the vascular compartment. Vascular underfilling triggers a series of hemodynamic and hormonal compensatory events such as an increase in cardiac output and plasma volume, activation of the renin-angiotensin-aldosterone and sympathetic nervous system and non-osmotic hypersecretion of antidiuretic hormone and sodium retention, all of which aim at refilling the vascular compartment. In patients with compensated cirrhosis, i.e. without ascites, compensatory events maintain blood volume despite vascular underfilling, and so these patients do not develop ascites. In patients with decompensated cirrhosis, vascular underfilling due to arterial vasodilation, together with a reduced oncotic pressure and a severe degree of portal hypertension, favours the development of ascites. Underfilling of the arterial circulation is at its maximum in functional renal failure and the hepatorenal syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Ascites↗
PubMed1991

Nonradical oxidants of the phagocyte type induce the activation of plasmatic single chain- urokinase.

Single chain- urokinase (scu-PA) is the proenzyme of the plasminogen activator urokinase (tcu-PA). In human blood scu-PA is of great stability. Activated phagocytes generate large amounts of single chain- urokinase and of reactive oxidants (chloramines and HOCl). Since these cells participate in physiologic fibrinolysis, we were interested in the interaction between plasmatic scu-PA and chloramines. The oxidants dose dependently induce the activation of plasmatic scu-PA. Optimal activation of scu-PA occurs at about 3-5 mmol/l of chloramine-T. The findings suggest a control mechanism of scu-PA stability/activity by oxidatively modifiable plasma proteins, such as alpha-2-antiplasmin. The oxidation mechanism seems to be mediated by singlet molecular oxygen, an excited oxygen species. Basing on this scu-PA/oxidant synergism a sensitive and fast functional assay of scu-PA in human plasma is presented. Plasmatic inhibitors normally interfering with functional scu-PA measurements are inactivated by addition of chloramine-T, imitating the physiological oxidants generated by activated phagocytes. The scu-PA concentration in plasma of n = 36 healthy individuals has been determined to be 5.8 +/- 1.6 ng/ml. The lower detection limit of plasma scu-PA by the procedure described is about 1.5 ng/ml of plasma. By means of this technique scu-PA concentration during thrombolytic therapy can be measured within minutes in undiluted (direct) plasma samples, allowing adjustments of the scu-PA dosage. The present study gives further credence for a role of singlet molecular oxygen, possibly a new type of locally acting hormones (autacoid), in the regulation of the fibrinolytic pathway.

Adult↗
PubMed1991

Platelet-activating factor (PAF) receptor-mediated calcium mobilization and phosphoinositide turnover in neurohybrid NG108-15 cells: studies with BN50739, a new PAF antagonist.

Platelet-activating factor (PAF) is an unusually potent lipid autacoid with a variety of biological activities. The growing body of evidence suggests that PAF might play an important role in modulation of central nervous system function, particularly during ischemia- and trauma-induced neuronal damage. However, the mechanisms involved in PAF actions on neuronal or other brain cells is virtually unknown. Therefore, this study was designed to characterize PAF receptor-mediated cellular signal transduction in neurohybrid NG108-15 cells with the aid of a new potent PAF antagonist, BN 50739. PAF induced an immediate and concentration-dependent increase in [Ca++]i with an EC50 of 6.8 nM. PAF-induced [Ca++]i mobilization was inhibited by several structurally unrelated PAF antagonists such as BN 50739, WEB 2086, SRI 63-441 and BN 52021, in a dose-dependent manner with IC50 values of 4.8, 6.9, 809 and 98500 nM, respectively. The calcium channel blockers nifedipine (5 microM) and diltiazem (10 microM) had no effect on the PAF-induced increase in [Ca++]i, but omission of CA++ from the incubation buffer caused an 82% reduction of PAF-induced [Ca++]i elevation; the remainder contributed from intracellular sources was completely inhibited by 10 microM TMB-8, an intracellular Ca++ blocker. NG108-15 cells exhibited homologous desensitization to sequential addition of PAF, but no heterologous desensitization between PAF and other agonists such as bradykinin, endothelin, angiotensin II and ATP was observed. PAF stimulated phosphoinositide metabolism in a dose-dependent manner with an EC50 of 5.1 nM for IP3 formation, which was also inhibited by the PAF antagonist BN 50739 in a dose-dependent manner (IC50 = 3.6 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗