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PubMed1981

Autacoids as modulators of the inflammatory and immune response.

Once considered only mediators of inflammation, autacoids, (histamine, prostaglandins and beta-mimetic catecholamines) have been found to be generated during specific early and late phases of immunity. They need sufficient concentrations to affect immunocytes and can modulate immunity usually by inhibiting it. Receptors for the autacoids on the immunocytes are nonrandomly distributed. A small portion of T suppressor cells always appear to have receptors on them, but precursor B cells and precursors of T cells that produce lymphokines or are responsible for cytolysis do not. Instead, as these cells mature they develop their autacoid receptors. With one exception, the function of the immunocytes is inhibited by the effects of autacoids. Again, in all but one instance, that inhibitory modulating effect is mediated by and directly proportional to the intracellular concentrations of cyclic adenosine monophosphate (AMP) generated by the autacoid. The clinical implications of these observations are beginning to be appreciated. One of them is that pharmacologic antagonists of the autacoids can have predictable but hitherto unanticipated effects on immune functions. It is inconceivable that these effects will not have clinical value.

Animals↗

PubMed1985

Pharmacologic effects of autacoids on subsets of T cells. Regulation of expression/function of histamine-2 receptors by a subset of suppressor cells.

Autacoids (principally histamine, beta adrenergic catecholamines, and prostaglandins E and A) have only recently been recognized as substantive moderators of a number of immune functions. If autacoids are to be considered as potential therapeutic immunomodulators, it is necessary to understand their effects on subsets of T cells while they are and are not in contact with each other. This report demonstrates that autacoid receptors are nonrandomly distributed on phenotypically and functionally distinct subsets of human T cells. Each human T cell subset responded to both histamine and isoproterenol, but the dose response curve and maximal efficacy varied widely between the subsets. The suppressor T cells were more responsive to both histamine and isoproterenol than helper/inducer T cells (TH) or cytotoxic T cells (Tc). We found that after mitogenic stimulation the response to histamine, but not isoproterenol, was greatly increased only in TH (Leu 3+) and Tc (Leu 2+, 9.3+) subsets, and that this effect may be regulated by suppressor T cells (Leu 2+, 9.3-). The dramatic rise in cAMP accumulation in response to histamine in mitogen-treated TH and Tc was totally blocked by an H2 antagonist (cimetidine), but not by an H1 antagonist (mepyramine). These findings indicate interdependence of (a) immunologically uncommitted subsets in their response to selected drugs, and (b) control of basal- and autacoid-induced cAMP production, as well as (c) increased qualitative and quantitative selectivity, which is caused by mitogen. If we had performed these experiments only on unseparated cells we would not have observed the remarkable selectivity of autacoid effects on subsets of T cells.

Autacoids↗

PubMed1989

The ocular effects of eicosanoids and other autacoids: historic background and the need for a broader perspective.

Great progress has been made in describing the synthesis of most known eicosanoids by ocular tissues. This progress has included identification of the spectrum of eicosanoids synthesized by different ocular tissues of different species, as well as comparisons of the relative proportion of individual eicosanoids produced by ocular tissues of different species. In contrast to this wealth of information, the lack of antagonists that are specific to individual eicosanoids has greatly hindered efforts to determine the specific ocular functions of each member of this family of autacoids. Furthermore, the absence of high-affinity ligands that are specific for individual eicosanoid receptors has greatly limited our ability to classify these receptors and to assign specific eicosanoid effects to specific cell types. In the early years of ocular PG research, the lack of recognition of the existence of parallel pathways of arachidonic acid metabolism and the lack of appreciation of the effects of some other autacoids--most notably the recently discovered neuropeptides--led to the premature conclusion that PGs have mediatory roles in a number of ocular pathophysiological responses. More recent studies have demonstrated that some ocular effects, such as chemotaxis, that were first attributed to classical PGs of the E and F type are actually mediated by eicosanoids synthesized by the lipoxygenase pathway, whereas other ocular responses, at least in some species, are mediated by various neuropeptides. These neuropeptides can be released by the same stimuli that cause the release of arachidonic acid. Furthermore, interpretation of the ocular effects of eicosanoids as well as neuropeptides has been complicated by large species differences in the effects of these autacoids on intraocular tissues. Among mammalian species, the rabbit eye and the primate eye may represent opposite extremes with respect to the extent of their responses to irritation and trauma, as well as with respect to their responses to some autacoids, especially eicosanoids and neuropeptides. In spite of these differences, the rabbit remains the animal most widely used in eye research. Consequently, many of the findings reviewed in this volume are also based on studies done only on rabbits. However, in view of the foregoing, we must resist the temptation to extrapolate to primates results obtained only from studies of rabbit eyes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1985

The effects of autacoids on cloned murine lymphoid cells: modulation of IL 2 secretion and the activity of natural suppressor cells.

The pharmacologic effects of histamine and isoproterenol (autacoids) were studied on clones of murine T helper (TH) and natural suppressor (NS) cells. The data are consistent with receptors for the autacoids being nonrandomly distributed on phenotypically and functionally distinct clones. The effects of histamine on IL 2 secretion by TH cells could be either inhibitory or stimulatory, depending on the conditions of incubation with the autacoid. When TH cells were pretreated with histamine, their secretion of IL 2 was augmented; conversely, if histamine was added to the TH cells in the presence of antigen, IL 2 secretion was inhibited. The suppressor function of NS cells was enhanced by preincubation with histamine (10(-4) M) for 4 hr before the washed NS cells were added to responder and stimulator cells in mixed lymphocyte cultures. Two H1 receptor antagonists, mepyramine (10(-6) M) and pyrobutamine (10(-7) M), each competitively blocked the histamine activation of the NS cells, but an H2 receptor antagonist cimetidine (10(-5) M) did not alter the suppressor-enhancing function of histamine. Activation of NS cells did not occur if histamine was added with responder, stimulator, and co-cultured cells in MLR. The effects of each autacoid were additive in cytolytic T cells alone. The adenylate cyclase pools that can be stimulated by isoproterenol and histamine in cytolytic T cells may be independent of each other, but further work will be needed to prove this point.

Animals↗

PubMed1992

Autacoids affecting vascular tone in the human fetal extracorporeal circulation.

1. The human fetal extracorporeal circulation is normally a vasodilated, low pressure system. 2. As this vasculature lacks innervation, autacoids have been postulated as being of great importance in controlling its tone. 3. This has now been confirmed by pharmacological in vitro techniques, particularly utilizing perfusion of the isolated umbilical cord and placental lobule. 4. The fetal umbilical-placental vessels are sensitive to a wide range of vasoconstrictor autacoids, some of which can cause intense vasospasm. 5. Thromboxane A2 receptors have been identified in both umbilical vein and placental villous vessels. 6. Prostacyclin and endothelial cell-derived relaxing factor (or nitric oxide) may be largely responsible for the low vascular resistance normally found in the fetal extracorporeal circulation. 7. Immediately after birth it is likely that stimuli such as cooling, stretching and handling of the umbilical cord cause release of eicosanoids and other autacoids from the vessels, leading to their complete closure.

Autacoids↗

PubMed1992

Studies of autacoid responsiveness and endothelium dependency in human umbilical arteries.

The effect of serotonin, prostaglandin E2 (PGE2) and PGF2 alpha on the smooth muscle tension in perfused human umbilical arteries was investigated before and after removal of the endothelium. Denudation was performed mechanically using a nylon filament loop, and the efficiency of the procedure was checked by electron microscopy. In non-denuded vessels the autacoids elicited biphasic pressure responses, all starting with a vasodilatation and followed by a strong vasoconstriction. After denudation no dilatatory responses were evoked, whereas the constrictory responses appeared to be unchanged. Pre-treatment of the vessels with methylene blue did not affect the autacoid responses. Generally the perfusion pressure decreased after the de-endothelialization, in some preparations to levels of about 50% of the initial perfusion pressure. In about one-third of the preparations exposure to methylene blue led to a definite pressure increase. The results indicate that endothelium-derived factors are involved in the autacoid responses and also in the maintenance of basic vascular tonus in the umbilical circulation.

Autacoids↗

PubMed1989

Mechanisms controlling the production of endothelial autacoids.

The endothelium plays an important role in the control of vascular tone and platelet activity. This is mainly achieved by the release of autacoids, particularly EDRF (identical with nitric oxide, NO) and PGI2. The release of both autacoids is evoked by physical factors like hypoxia and shear stress and by various chemical compounds like acetylcholine, ATP and bradykinin. These agonists bind to membrane receptors coupled to phospholipase C, thereby increasing production of inositol-1,4,5-trisphosphate (IP3). IP3 mobilizes Ca2+ from intracellular stores, thus elevating the intracellular free calcium concentration ([Ca2+]i), in synergy with a simultaneously induced transmembrane Ca2+ influx. The level of [Ca2+]i closely correlates with endothelial production of PGI2 whereas Ca2+ influx is apparently a decisive signal for the sustained release of EDRF. This influx may be facilitated by an agonist-induced membrane hyperpolarization probably being mediated by activation of Ca2+-dependent K+ channels. Depolarization of the endothelial cell membrane on the other hand (evoked by raising the extracellular K+ concentration) attenuates the Ca2+ influx as well as EDRF release. The agonist-induced endothelial hyperpolarization may also be electrotonically transmitted to adjacent smooth muscle cells via myoendothelial gap junctions and may act synergistically with the EDRF-mediated relaxation. Alternatively, spread of this electrical signal along the endothelial lining may enhance the release of autacoids.

Animals↗

PubMed1987

Changes in the biological activity of autacoids during passage through the human perfused fetoplacental lobule.

Changes in the biological activities of a number of autacoids after a single passage through the human perfused fetoplacental lobule have been assessed by bioassay, whilst recording fetal vascular resistance. Bradykinin did not affect vascular resistance, but its biological activity on the superfused bioassay tissues fell by approximately 98%, whereas des-Asp1-angiotensin I activity increased at least 80-fold and the vascular resistance rose. All these effects were inhibited by captopril. Angiotensin II increased vascular resistance but its activity on the bioassay tissues was not changed. 5-Hydroxytryptamine activity was reduced by 67-90% and resistance to flow was not affected. The activities of prostaglandins D2, E2, and F2 alpha were slightly reduced. Prostaglandins D2 and F2 alpha caused vasoconstriction, their maximum effects being greater than those of either of the angiotensins. The TxA2-mimetic U46619 was approximately 90 times more potent than PGF2 alpha, as a vasoconstrictor, but the maximal effects were comparable. Thus, autacoid activity can be reduced, augmented or not affected during passage through the human perfused fetal placental vasculature.

Angiotensin I↗

PubMed1989

The evocation of rumination in sheep by the close-arterial injection of catecholamines, cholinergic drugs, autacoids and gastrointestinal hormones into the forestomach.

The effect of alpha-2 adrenoreceptor agonists, cholinergic drugs, autacoids and some gastrointestinal hormones upon the evocation of rumination in sheep when injected by close-arterial injection into the forestomach was examined. Apart from adrenaline, noradrenaline, dopamine and xylazine only one alpha-2 agonist (BHT933) evoked rumination effectively. Acetylcholine, neostigmine, the gastrointestinal hormones and the autacoids examined did not evoke rumination consistently. Tyramine did not usually evoke rumination and guanethidine injected before adrenaline did not prevent the latter from evoking rumination. The evocation of rumination by catecholamines does not appear to involve sympathetic, cholinergic or non-sympathetic non-cholinergic neurones in the enteric nervous system to activate the nervous sensory receptors involved in the reflex evocation of rumination.

Animals↗

PubMed1984

Effects of vasoactive autacoids on the human umbilical-fetal placental vasculature.

Studies have been made of the effects of autacoids on vascular tone of the human perfused fetal umbilical vein and placental lobule. The thromboxane A2 (TxA2)-mimetic substance U46619, 5-hydroxytryptamine and bradykinin were powerful constrictors of the vein. Prostaglandins E2 (PGE2), F2 alpha (PGF2 alpha), adrenaline, noradrenaline, histamine and angiotensin II were much less potent. Venoconstriction caused by U46619, bradykinin and 5-hydroxytryptamine was reduced during inhibition of phospholipase A2 with mepacrine. Responses to U46619 were also reduced after inhibition of cyclo-oxygenase with indomethacin whereas those to bradykinin and 5-hydroxytryptamine were potentiated. In the placenta U46619 was the most potent vasoconstrictor, bradykinin, 5-hydroxytryptamine, angiotensin II, PGE2 and PGF2 alpha being 10-100 times less active. Responses to U46619 were reduced by either mepacrine or indomethacin. Arachidonic acid caused umbilical venoconstriction but vasodilatation in the placenta. Both effects were reduced by indomethacin. Prostacyclin (PGI2) caused vasodilatation in both preparations. It is suggested that TxA2 in the placenta and TxA2, 5-hydroxytryptamine and bradykinin in the umbilical vein could contribute to control of vascular smooth muscle tone. Their vasoconstrictor effects are partly indirect and affected by the concomitant local release of eicosanoids. The results add support to previous conclusions that these autacoids may normally have important influences on blood flow in the fetal extra-corporeal circulation. Agents inhibiting their synthesis, eg non-steroidal anti-inflammatory agents, should only be prescribed during pregnancy with these facts in mind.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1986

Autacoids and some mediators in allergic and non allergic forms.

The aim of this review is that to examine some among the most important mediators involved in the onset of autacoid-mediated allergic and non-allergic symptomatology. Autacoids, such as histamine and arachidonic acid derivatives (leukotrienes and prostaglandins), mediators derived from cell membrane, such as PAF-acether and other cell-derived mediators, such as PF4, are described. Special importance is given to the respective pharmacological actions and to the mechanisms by which these actions are performed (receptors, antagonisms, synergism) from whose complexity systemic reactions might ensue. Furthermore, a part of this study is dedicated to the complex interactions among biochemical systems of the body such as Kinins, Coagulation, Fibrinolysis and Enzymatic Activity Mediators that can interfere with these interactions and support some pathologies. Besides, a chapter is devoted to Neurogenic Inflammation and therefore to Substance P and other neuropeptides.

Animals↗

PubMed1986

Autacoid binding to serum proteins. Interaction of platelet activating factor (PAF) with human serum alpha-1-acid glycoprotein (AAG).

Platelet activating factor (PAF; 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent bioactive phospholipid released from platelets, neutrophils, basophils and macrophages that has been proposed as a mediator of anaphylaxis, acute lung injury and other disorders. Specific factors which stabilize PAF and/or regulate PAF activity in body fluids are largely unknown. As part of a general autacoid-serum protein binding screen, the platelet activating factor-alpha-1-acid glycoprotein (PAF-AAG) interaction was indirectly characterized by examining the ability of PAF to displace propranolol from AAG. Both PAF and its deacetylated metabolite (lyso-PAF), at 20 microM, doubled the fraction unbound of propranolol (0.4 microM) from purified human AAG (20 microM). None of the other autacoids that were studied (epinephrine, serotonin, spermidine, putrescine, leu-enkephalin or phenethylamine) exhibited any propranolol displacement activity. Scatchard analysis indicated that PAF competitively displaced propranolol from AAG, causing the apparent affinity constant for propranolol-AAG to decrease from 1.8 X 10(5) M to 6.9 X 10(4) M. PAF behaved qualitatively like chlorpromazine (a documented inhibitor of propranolol binding to AAG), but PAF was less effective at displacing propranolol. The apparent binding to AAG may help stabilize and transport extracellular PAF. Furthermore, the interaction of PAF and AAG suggests that serum AAG, which fluctuates in a number of diseases, may function to regulate PAF activity during acute and chronic disease states.

Binding, Competitive↗

PubMed1991

Effect of autacoid modulation on N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity.

N-(3,5-Dichlorophenyl)succinimide (NDPS) is an agricultural fungicide which has been shown to induce acute tubular necrosis. The purpose of the present study was to determine if creatinine clearance was altered early in the development of NDPS nephrotoxicity. This study also examined the effect of autacoid modulation on the renal effects induced by NDPS and two metabolites of NDPS, N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA). In one set of experiments, male Fischer 344 rats (4 rats/group) were administered a single intraperitoneal (i.p.) injection of NDPS (1.0 mmol/kg) or vehicle and creatinine clearance was determined at 3 and 6 h post-treatment. NDPS administration resulted in a marked decrease in creatinine clearance at both time points. In a second set of experiments, rats (4-8 rats/group) were pretreated with the cyclooxygenase inhibitor indomethacin (3.0 or 5.0 mg/kg, i.p.) or the thromboxane synthase inhibitor dazmegrel (20 mg/kg, i.p.) 1 h before the i.p. administration of NDPS (0.2 or 0.4 mmol/kg), NDHS (0.05 or 0.1 mmol/kg), NDHSA (0.05 or 0.1 mmol/kg) or vehicle. Indomethacin pretreatment potentiated the nephrotoxic potential of NDPS and its two metabolites, while dazmegrel pretreatment attenuated NDPS nephrotoxicity without marked effects on NDHS or NDHSA nephropathy. These results indicate that renal hemodynamic changes occur early in the development of NDPS nephrotoxicity and that autacoids are important modulators of NDPS- and NDPS metabolite-induced renal effects.

Animals↗

PubMed1992

Release of contracting autacoids by aortae of normal and atherosclerotic rabbits.

The aim of our study was to examine the release of various lipid and peptide contracting autacoids by aortae of normal and atherosclerotic rabbits. Leukotriene (LT) E4, an enzymatic derivative of LTC4, thromboxane (Tx) B2, and endothelin-1 (ET-1) were measured by radioimmunoassay techniques in aortic preparations of normal and cholesterol-fed rabbits. Intact aortae of normal rabbits incubated with the calcium ionophore A23187 for 1 h at 37 degrees C released LTE4 and TxB2 (22 +/- 3.5 and 14.8 +/- 2 pg/mg of tissue, respectively, mean +/- SEM, n = 33). Removal of aortic endothelium was associated with a significant reduction in LTE4 (44%) and TxB2 (58%) release. In aortic preparations from cholesterol-fed rabbits, the release of LTE4 was significantly enhanced (41 +/- 8 pg/mg of tissue, mean +/- SEM, n = 27) whereas TxB2 was not significantly altered. No detectable amounts of ET-1 were measured after 1 h of incubation. However, at 4 h, an endothelium-dependent release of ET-1 from normal aortae was demonstrated. In atherosclerotic aortae, ET-1 release was significantly higher than in controls (10 +/- 1.3 vs. 5 +/- 0.5 pg/cm2, mean +/- SEM, n = 16). We conclude that enhanced formation of vasoconstrictor autacoids may contribute to altered vasomotion of atherosclerotic blood vessels.

Animals↗

PubMed1992

Involvement of renal autacoids in the direct effects of mixed amino acids on the kidney.

A pharmacological approach has been employed to investigate the involvement of renal autacoids in the direct effect of amino acids on the isolated rat kidney. The increase in renal perfusate flow induced by 6 mM mixed amino acids was inhibited by sulpiride, a dopamine antagonist. The change in GFR induced by 6 mM mixed amino acids was abolished by L-nitro-arginine methyl ester, an inhibitor of nitric oxide biosynthesis and partially inhibited by either sulpiride or indomethacin. It is concluded that several autacoids may mediate the direct effect of amino acids on the kidney with dopamine being primarily involved in hyperperfusion and nitric oxide involved primarily in hyperfiltration.

Amino Acids↗

PubMedDate not supplied

A model of cytosolic calcium regulation and autacoids production in vascular endothelial cell.

A model of vascular endothelial cell is proposed to describe the mechanisms by which cytosolic calcium (Cai) is modulated and endothelium-derived relaxing factor (EDRF) and prostacyclin (PGI2) are released when the cell is stimulated by agonist. The intracellular Ca2+ store of the model cell is comprised of a superficial (sc) and a deep (dc) compartment. The dc Ca2+ content is refilled by the sc whose [Ca2+] is the same as extracellular Ca2+. Inositol (1,4,5)-trisphosphate (IP3) produced by agonist modifies the dc permeability which discharges its Ca2+ to the cytosol. The increase of Cai induces Ca2+ released from the sc. Ca(2+)-activated K+ current hyperpolarises the cell. The raised Cai releases PGI2 in the presence of IP3 while EDRF is released by Cai. The model explains satisfactorily the Ca2+ transient and autacoids production of the aortic endothelial cell without the need of calcium influx from extracellular space. The cytoplasmic Ca2+ oscillations observed in human endothelial cell from umbilical veins were reproduced by the model. Production of EDRF by the artery due to increase in pressure was also simulated.

Autacoids↗

PubMed1979

Reactivity of isolated canine bronchus and pulmonary blood vessels to autonomic, autacoid agents and antigen.

Adult dogs were sensitized to horse plasma. Reactivity of isolated bronchus and pulmonary blood vessels to antigen and some selected autonomic and autacoid agents were studied. Pulmonary veins contracted to bradykinin, 5-HT, PGF2alpha, PGE2, histamine, carbachol and antigen (Schultz-Dale reaction). Pulmonary arterial strips contracted to 5-HT and histamine, but only weakly to horse plasma. Bronchial strips contracted to carbachol, 5-HT, histamine and horse plasma, relaxed to isoprenaline, PGE1 and PGE2. Subsequent antigen challenge produced 'desensitization'. Allowing the tissues to 'rest' for 1 and 2 h resulted in partial 'recovery' of the anaphylactic response. This investigation suggests that the contractions of sensitized pulmonary vein and bronchus to specific antigen may contribute to the patho-physiology of pulmonary hypersensitivity in dogs.

Anaphylaxis↗

PubMed1982

Autacoid and autonomic reactivity of sheep lung parenchymal strip and its modification by antigenic sensitization.

Lung parenchymal strips (LPS) of horse plasma-sensitized and control sheep were studied isometrically in isolated organ baths and their responses to autacoid and autonomic agents were compared. Control LPS responded with contractions to histamine greater than carbachol greater than 5HT and relaxed to isoproterenol greater than adrenaline greater than phenylephrine. In sensitized LPS, adrenaline and phenylephrine-induced relaxations were converted to contractions and a new order of potency and efficacy for spasmogens was observed i.e. histamine greater than carbachol greater than adrenaline greater than phenylephrine greater than 5HT. Isoproterenol was also significantly (P less than 0.05) less potent and less effective in relaxing sensitized LPS compared to controls. Mepyramine, atropine and propranolol competitively antagonized their respective agonists (i.e. histamine, carbachol and isoproterenol) confirming the presence of H1-histaminergic, muscarinic-cholinergic and beta-adrenergic receptors respectively. The conversion of the relaxant effect of adrenaline and phenylephrine to a contraction supplemented by a significant reduction in isoproterenol activity suggests an impairment in the effective ratio of beta: alpha adrenoceptors in ovine LPS subsequent to antigenic sensitization.

Animals↗