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PubMed1993

[Resting tonus of isolated airway smooth muscles].

The regulation of airway caliber is important for supporting the physiological respiratory function and is considered to be mainly controlled by the central and peripheral nervous systems. In the present review, we discussed the resting tonus of the isolated airway smooth muscle of the guinea pig and compared it with that of the human; the former is similar to the latter because both are well-developed in the airway and well-responsive to a variety of mediators. The resting tonus of the isolated guinea pig trachea is largely decreased by indomethacin, a cyclooxygenase inhibitor, while that of the isolated human bronchus is increased following transient decrease by indomethacin. Furthermore, the human bronchus is markedly decreased by not only a selective peptide leukotriene antagonist, MCI-826, but also 5-lipoxygenase inhibitors, AA 861 and cirsiliol. These results indicate that contractile prostanoid(s) and peptide leukotrienes are possible mediators for the maintaining the resting tonus of the respective preparations. Both preparations still have a small but substantial part of the resting tonus resistant to these drugs, the mediator(s) responsible for which is not clarified yet. In short, arachidonate metabolites are major candidates for the resting tonus of either isolated guinea pig or human airway smooth muscle and may contribute to at least a part of the regulation of the airway caliber as autacoids in vivo.

Animals↗
PubMed1993

[Cellular reactions after stimulation of receptors: research model for evaluation of effects and action mechanisms of drugs for discovery of innovative drugs].

When cellular stimulants such as neurotransmitters, hormones, autacoids, cytokines and growth factors stimulate their respective specific receptors in the plasma membranes of cells, a variety of responses are elicited. GTP-binding proteins are also involved in the reactions between receptors and cellular effectors. Stimulation of receptors are subsequently coupled to the activation of ion channels, turnover of inositol phospholipid metabolism, adenylate cyclase and guanylate cyclase, inhibition of adenylate cyclase and potentiation of all proliferation. Active substances such as the so-called second messengers are produced in the cells. In this article, two findings are described: 1) Ca2+, which increases by stimulation of receptors with neurotransmitters and hormones, stimulated Ca2+/calmodulin-dependent protein kinase II in cell systems such as NG108-15 neuroblastoma x glioma hybrid cells and primarily cultured neuronal cells of rat hippocampus. 2) Coupling preferences and possible transduction mechanisms from experiments on NG108-15 cells and NL308 neuroblastoma x fibroblast hybrid cells which have been stably transfected with DNA for m1, m2, m3 and m4 muscarinic acetylcholine receptors were examined. These results may provide a useful research model for examining and evaluating the effects and mechanisms of the drugs on a living system and may help develop useful methodology for the discovery of innovative drugs.

Animals↗
PubMed1997

[Signaling to nuclear transcription factors in the brain].

In eukaryotes, protein de novo synthesis is mainly controlled at the level of gene transcription by transcription factors in cell nuclei. Transcription factors are nuclear proteins with abilities to recognize particular nucleotide sequences at promoter or enhancer regions on double stranded DNAs, followed by modulation of transcription of their inducible target genes. These transcription factors are categorized into 3 different major classes according to their unique protein motifs. In this article, we have outlined the signal responsiveness of particular transcription factors in the brain. Indeed, nuclear transcription factors rapidly respond to a variety of extracellular signals carried by neurotransmitters, hormones and autacoids as a third messenger in frequent situations. Moreover, delayed neuronal death could involve mechanisms associated with modulation of de novo synthesis of target proteins by the transcription factor activator protein-1 in particular hippocampal subregions after ischemia. Accordingly, it thus appears that transcription factors may play a critical role in long-lasting consolidation of transient signals through modulation of de novo synthesis of inducible target proteins in the brain.

Animals↗
PubMed1979

[Cathartic activity of spasmogens in mice, rats and guinea pigs (author's transl)].

To examine the effect of spasmogens on propulsive motility in the intestine, cathartic activity of drugs was investigated. Mice, rats and guinea pigs were individually observed in cages with 20 separate small rooms in which a sheet of filter paper covered the botton of case for observation of feces. The effect was evaluated 1 hr after drug administration. Cathartic activity of spasmogens was the most marked in mice followed by rats, but was rarely observed in guinea pigs. Cholinergic drugs and cholinesterase inhibitors had a cathartic effect in mice and rats, but the activity differed. Drugs such as acetylcholine and physostigmine produced a low cathartic activity even at sublethal and lethal doses. Other drugs as bethanechol, pilocarpine and neostigmine had a dose dependent cathartic effect at doses below lethal ones and were found to be clinically useful for intestinal relaxation after laparotomy. Among autacoids which contract the intestine by direct action on smooth muscles, histamine and bradykinin had no cathartic effect in mice and rats. 5-HT and prostaglandin E2 were dose dependent with a marked cathartic effect in both species. 5-HTP produced the same cathartic activity as that seen with 5-HT in mice, but had no cathartic effect in rats. The cathartic effect of BaCl2 was low, but dose dependent in both species. We recommend this method for the study of the effect of various compounds on the propulsive motility of the intestine.

Amines↗
PubMed1989

[Pharmacology of prostaglandins; their profile and characterization in the body].

Arachidonic acid metabolites, prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), are classified as a type of autacoids. They are not stored in the cells, but stored as a precursor acid, arachidonic acid, in membrane phospholipids. Various physiological stimuli activate phospholipase A2 and release arachidonic acid, which is converted to 1 or 2 products by related enzymes within a few minutes, depending upon individual cell functions. The metabolites are readily inactivated in aqueous solution and in the body. The structures of the various metabolites are quite similar, but their pharmacological actions vary from metabolite to metabolite and some exert opposite actions to those of others. The metabolites play some pivotal roles in physiological or pathophysiological responses such as pain sensation, fever, plasma leakage and skin erythema. Thus, non-steroidal anti-inflammatory drugs, like aspirin, exert their actions through cyclooxygenase inhibition at low doses. PGE2 can be detected in the exudate of acute inflammatory models, and the simultaneous release of PGE2 with bradykinin induces a large increase in plasma leakage and triggers exudate accumulation. LTB4 induces extravasation of PMN leukocytes at the microcirculatory level and is generated in the reperfused area of infarcted cardiac tissue after ligation of rat coronary artery, but in the latter case, the leukocyte migration was not solely induced by LTB4, which was replaced by a complement component (C5a). LTC4 may be involved in ethanol injury of the gastric mucosa and endogenous PGE2 prevents this injury. The real roles of individual arachidonic acid metabolites have been gradually disclosed, but most of the roles are still yet to be clarified.

Animals↗
PubMed1983

Immunopharmacological studies of sodium copper chlorphyllin (SCC).

Effect of sodium copper chlorophyllin (SCC) on experimental allergic reaction was investigated. IgE antibody mediated reactions, homologous passive cutaneous anaphylaxis (PCA) in rats and the release of anaphylactic mediators (histamine and/or slow reacting substance of anaphylaxis (SRS-A] from sensitized guinea pig lung tissues or rat peritoneal mast cells classified as a Type I reaction were clearly inhibited by SCC at a similar potency as N-(3',4'-dimethoxy cinnamoyl) anthranilic acid (N-5'). The increase of vascular permeability in rat skin caused by autacoids or enzymes that participate in the Type I reaction was also inhibited by SCC. Type II or III, complement dependent, reactions including reversed cutaneous anaphylaxis (RCA) in rats and Forssman cutaneous vasculitis (FCV) in guinea pigs were inhibited by SCC. Prednisolone inhibited RCA in rats, but did not inhibit FCV in guinea pigs. Two experimental types of glomerulonephritis, nephrotoxic serum (NTS) nephritis in rats and immune complex nephritis in (NZW X NZB) F1 mice, in which Type II and III reactions might participate in the onset and the development of the disease, were slightly inhibited by SCC in terms of the biochemical changes of blood and urine parameters and histopathological scores. A moderate remission of the onset and development of these two experimental types of nephritis was recognized by the administration of prednisolone. Delayed hypersensitivity reaction as a Type IV reaction caused by sheep red blood cells (SRBC) in sensitized mouse footpad was not affected by SCC. Prednisolone clearly inhibited the SRBC induced footpad reaction in mice. IgM antibody production in mice and IgE antibody production in rats were not influenced by daily injection of SCC.

Animals↗
PubMed1990

Assessment of vascular permeability increase in the mouse by dye leakage during paw edema.

Vascular permeability increase induced by histamine, bradykinin, platelet-activating factor (PAF), or phorbol myristate acetate (PMA) in the mouse paw was assessed by the dye leakage method. The amount of dye extracted from the paw showed a clear dose-response relationship to the dose of each agonist injected into the paw. Among the autacoids used, PAF showed the most potent activity in the mouse paw. The results are consistent with those seen in the rat dorsal skin as previously reported. Involvement of histamine, 5-hydroxytryptamine and PAF is suggested in the vascular permeability increase induced by PMA in the mouse paw.

Animals↗
PubMed1991

Pharmacomechanical coupling in vascular smooth muscle cells--an overview.

In vascular smooth muscles, neurotransmitters or autacoids produce contraction through activation of Ca2(+)-influx and release of Ca2+ from intracellular store sites. These agonists appear to activate Ca2(+)-influxes in both voltage-dependent and voltage-independent manners. The release of Ca2+ is though to be linked to the action of inositol 1,4,5-trisphosphate. The phosphorylation of myosin light chain may be the mechanism for the Ca2(-+)-induced contraction in smooth muscles. Some agonists only transiently increase cellular Ca2+ and the phosphorylation of myosin, but they produce a sustained contraction in various vascular tissues. Hence, additional high Ca2(+)-sensitive mechanisms are no doubt involved in the contraction of vascular smooth muscle. In the present article, attention will be directed to the mechanisms and agonist-induced contraction in arterial smooth muscle.

Amino Acid Sequence↗
PubMed1994

Characteristics of the responses of isolated and perfused canine splenic arteries to vasoactive substances and to periarterially electrical stimulation.

Pharmacological characteristics of the canine isolated splenic artery were investigated by the cannula insertion method for observing vascular responses to vasoactive agents and periarterial nerve stimulation. Four alpha-adrenoceptor agonists and tyramine induced vasoconstrictions in a dose-dependent manner, and the order of potency was noradrenaline (NA) > phenylephrine > clonidine > methoxamine > tyramine. Xylazine (a selective alpha 2-adrenoceptor agonist) did not elicit any vasoconstriction. Several autacoids and KCl also constricted the splenic artery dose-dependently, and the order of potency was 5-hydroxytryptamine (5-HT) >> ATP = histamine >> KCl. The dose-response curves for clonidine and NA were shifted to the right by bunazosin (a selective alpha 1-adrenoceptor antagonist), but were not affected by midaglizole (a selective alpha 2-adrenoceptor antagonist). The parameters of electrical stimulation to elicit a clear and constant vasoconstriction were 0.2 msec of pulse duration, 6 V and 0.1 Hz. The vasoconstrictive responses to electrical stimulation at 6-12 V, 0.1-10 Hz and 0.2-1 msec of pulse duration were completely inhibited by tetrodotoxin (TTX) and strongly inhibited by guanethidine. The results in this study suggest that: 1) in contrast with other regional arteries, the canine splenic artery has an alpha 1-adrenoceptor-related and clonidine-sensitive vasoconstrictive response, 2) this artery has no functional postsynaptic alpha 2-adrenoceptors, 3) it may be easier to observe the vascular responses to vasoactive agents in the isolated and perfused arterial segments, and 4) the isolated and perfused canine splenic artery is useful as a preparation to study the sympathetic nerve transmission.

Adrenergic alpha-Agonists↗
PubMed2001

Roles of muscarinic acetylcholine receptors in interleukin-2 synthesis in lymphocytes.

Receptors for many neurotransmitters including catecholamines and acetylcholine (ACh) have been detected on the cell surface of lymphocytes. It has been demonstrated that a human T cell line synthesizes ACh and suggested that ACh may be an autacoid modulating T cell-dependent immune responses. However, the biochemical interactions of the ACh system with the immune system have not been elucidated in detail. We have shown that m1 and m2 muscarinic receptor mRNAs are expressed in human peripheral blood lymphocytes and in human T cell line Jurkat cells and that pretreatment of these cells with a muscarinic receptor agonist enhances interleukin-2 (IL-2) production. We also postulated possible intracellular signaling pathways via which muscarinic receptors regulate IL-2 production in Jurkat cells. The findings suggest that M1 muscarinic receptors are involved in muscarinic receptor-mediated enhancement of IL-2 production in Jurkat cells and that the transcription factor AP-1 and pathways via mitogen-activated protein kinase (MAPK)/extracellular signal regulated protein kinase and c-Jun N-terminal kinase, but not via p38 MAPK, may be involved in the muscarinic receptor-mediated enhancement of IL-2 production. Our findings demonstrate a neuro-immune interaction through muscarinic receptor signaling in immune cells.

Humans↗
PubMed2002

Transcription factors and drugs in the brain.

In mammalian cells, protein de novo synthesis is mainly regulated at the stage of gene transcription by RNA polymerase II in the nucleus. Transcription factors are proteins that bind to the specific nucleotide sequences at promoter or enhancer regions on target genes to control the transcription of mRNA from genomic DNA. In this article, we have outlined the signal responsiveness of different transcription factors to particular drugs in the brain. Nuclear transcription factors rapidly respond to a variety of extracellular signals carried by neurotransmitters, hormones and autacoids as a third messenger in frequent situations. Translated proteins are responsible for a number of physiological and pathological events for a long period in the brain. We have also discussed possible involvement of transcription factors in molecular mechanisms underlying development of tolerance and dependence to drugs following acute and chronic administration.

Animals↗
PubMed2004

[Thrombin: antithrombotic properties and pharmacological consequences].

During the last few years, the availability of endothelial cell cultures isolated from different vascular regions contributed to a significant increase in understanding the complex pro- and antithrombotic mechanisms in our circulatory system. The most important key enzyme is thrombin. Due to its haemostatic properties this serin protease catalyzes fibrin formation, activation of factors V, VIII and XIII as well as irreversible platelet aggregation. These processes may occur even within the circulatory system in case of endothelial stimulation (e. g. by inflammation mediators) for expression of binding sites for factors IX, IXa, X, Xa, von Willebrand protein and PAF. Thus not only catalytically activated coagulatory cascades, but also enhanced cooperation of platelets and granulocytes will occur. Paradoxically, in low intravascular concentration, thrombin, in combination with a healthy endothelial layer, may be the critical factor for the inhibition of thromboses. Respective antithrombogenic properties will mainly affect pre-venous microvascular circulation. In detail, they include thrombin-induced endothelial formation of antiaggregatory autacoids from platelet release products, anticoagulatory activation of protein C and absorption of active coagulation factors at endothelial heparan/ATIII complexes as well as release of profibrinolytic plasminogen activator of endothelial origin. The understanding of these complex regulatory functions enables not only a critical evaluation of actually discussed haemostasiologic risk factors (enhanced platelet reactivity, high concentrations of factor VII, VIII, fibrinogen, PAI, ATIII), but also the development of new pharmacologic strategies for prevention of thrombosis.

Antithrombins↗
PubMed2003

Adenosine receptors as targets for drug development.

Adenosine is a ubiquitous autacoid that acts on four defined receptors, named A(1), A(2A), A(2B) and A(3). Although the biological activity of adenosine has been known for more than 70 years and the existence of specific receptors for more than 25 years, it is only now that the full potential for drug development is becoming clear. Among some of the conditions for which adenosine receptor-based therapy might be used are Parkinson's disease, hypoxia/ischemia, epilepsy, kidney disease and asthma.

Adenosine↗
PubMed2004

Production of prostaglandin D(2) by human osteoblasts and modulation of osteoprotegerin, RANKL, and cellular migration by DP and CRTH2 receptors.

UNLABELLED: Human osteoblasts produce PGD(2), which acts on the DP receptor to decrease osteoprotegerin production and on the CRTH2 receptor to decrease RANKL expression and to induce osteoblast chemotaxis. These results indicate that activation of CRTH2 may lead to an anabolic response in bone. INTRODUCTION: Whereas the actions of prostaglandin (PG)E(2) as a modulator of bone and osteoblast function are relatively well characterized, little is known about PGD(2) and bone metabolism. The objectives of this study were to determine if human osteoblasts can produce PGD(2), which prostaglandin D(2) synthases are implicated in this synthesis, to identify the PGD(2) receptors (DP and CRTH2) on these cells and to characterize the biological effects resulting from their activation. MATERIALS AND METHODS: RT-PCR analysis and immunohistochemistry were used to detect PGD(2) receptor and synthases in cultured human osteoblasts. Immunohistochemistry was used to identify the synthases and receptors in human bone tissue. Intracellular cAMP and calcium levels were determined to verify receptor activation. The cells were stimulated with PGD(2) or the specific agonists BW 245C (DP) and DK-PGD(2) (CRTH2), and the resulting effects on osteoprotegerin (OPG) secretion, RANKL expression, and chemotaxis were determined. Osteoblast production of PGD(2) was evaluated by measuring PGD(2) in the culture supernatants after stimulation with interleukin (IL)-1, TNF-alpha, PTH, vascular endothelial growth factor (VEGF), and insulin-like growth factor I (IGF-I). RESULTS: Human osteoblasts in culture generated PGD(2) when stimulated. Both osteoblasts in culture and in situ present the lipocalin-type PGD(2) synthase only. Both DP and CRTH2 receptors were present in human osteoblasts in culture and in situ. Stimulation of DP resulted in an increase in cAMP, whereas CRTH2 increased the intracellular calcium level. OPG production was reduced by 60% after DP receptor stimulation, whereas CRTH2 receptor stimulation decreased RANKL expression on human osteoblasts. As reported for other cell types, CRTH2 was a potent inducer of chemotaxis for human osteoblasts in culture. CONCLUSIONS: Human osteoblasts in culture produce PGD(2) under biologically relevant stimuli through the lipocalin-type PGD(2) synthase (L-PGDS) pathway. As an autacoid, PGD(2) can act on DP and CRTH2 receptors, both present on these cells. Specific activation of CRTH2 could lead directly and indirectly to an anabolic response in bone.

Bone and Bones↗
PubMedDate not supplied

Regulation of mast cells by beta-agonists.

The human lung mast cell is known to be a critical effector cell in the mediation of asthma. Activation of the mast cell by allergens and other stimuli leads to the release and generation of a wide variety of autacoids that cause bronchoconstriction, promote inflammation, and may influence airway remodeling. Therefore, the stabilization of mast cells has obvious value in the prevention of asthma. Among the drugs used to treat asthma, only beta-agonists are effective stabilizers of mast cells. Both short- and long-acting beta-agonists are effective against mast cells, but there are differences between agonists regarding the extent of inhibitory activity attained. Consequently, the type of beta-agonist prescribed influences the degree of mast cell stabilization possible. Despite the potential value of attenuating mast cell activity with beta-agonists, this benefit may diminish with time because of the development of tolerance. Both short- and long-acting beta-agonists can induce tolerance to mast cell stabilization, and generally, higher efficacy agonists tend to induce greater levels of tolerance; however, weaker agonists induce greater levels of tolerance than might be expected. Tolerance to the mast-cell-stabilizing effects of beta- agonists may be an issue clinically, because this occurs more readily than tolerance to smooth muscle relaxation. This could lead to a situation in which beta-agonists fail to prevent the release of mediators from mast cells but can still effectively relax airway smooth muscle. The continued ability to bronchodilate could mask the unfavorable consequences of unchecked mediator release from mast cells.

Adrenergic beta-Agonists↗
PubMed1988

Platelet-activating factor in the rabbit uterus during early pregnancy.

Platelet-activating factor (PAF) concentrations were low in the non-pregnant, oestrous uterus (mean +/- s.e.m.: 2.2 +/- 1.2 pmol/g, n = 3). However, uterine PAF increased dramatically during pregnancy to a maximum of 37.8 +/- 4.90 pmol/g (n = 7) on Day 5. By Day 7, PAF concentrations in the uteri of pregnant rabbits had returned to levels similar to those found at oestrus. In contrast, uterine PAF in pseudopregnant rabbits peaked at 30.6 +/- 2.8 pmol/g (n = 8) on Day 4, declined to 20.5 +/- 2.4 pmol/g (n = 8) on Day 5 and then remained at that concentration through Day 7. Uterine PAF co-migrated with synthetic PAF (1-O-hexadecyl-2-acetyl-sn-glycero-phosphocholine) in both thin-layer and normal-phase high-performance liquid chromatography. PAF activity in the uterus during pregnancy and pseudopregnancy was found almost exclusively in the endometrium; little or no PAF was found in myometrium, uterine flushings or blastocysts. While no PAF was detected in blastocysts on Days 5 and 6 of pregnancy, the presence of the embryo appears to modulate biosynthesis and/or degradation of PAF by the uterus, since PAF decreased significantly in uterine tissue apposed to the implanting embryo (but not in similar areas between such attachment sites). Increased concentrations of PAF in the preimplantation rabbit uterus followed by a dramatic decrease on the day of blastocyst attachment suggest that this potent inflammatory autacoid may play a vital role in implantation.

Animals↗
PubMed1989

Role of platelet-activating factor (PAF) in the initiation of the decidual reaction in the rat.

Injection of PAF into the left uterine horn induced a dose-dependent decidua-like reaction in the pseudopregnant rat. This reaction was maximal when PAF was injected at Day 5 of pseudopregnancy and was blocked by the specific PAF antagonist, BN 52021. BN 52021 did not interfere with the decidual reaction induced by prostaglandin E-2 or insertion of a cotton thread in the uterine horn. In contrast, a decidua-like reaction was not evoked by the inactive lyso-PAF, demonstrating the specificity of the action of PAF. The decidua-like reaction induced by PAF involves the generation of cyclooxygenase metabolites of arachidonic acid since it was inhibited by indomethacin. The histological alterations induced by PAF were similar to those observed after embryo implantation, strengthening the postulate for a role of the autacoid in the early stages of pregnancy.

Animals↗
PubMed1992

Signal transduction in mesangial cells.

Phenotype, growth, and functional characteristics of glomerular mesangial "myofibroblasts" are under the control of multiple hormones, vasoactive agents, autacoids, and cytokines. Several parallel signal transduction pathways couple receptor occupancy with functional changes, including phospholipases C, A2, and D breakdown of membrane phospholipids, and adenylate/guanylate cyclase activation. Changes of cytosolic ion concentrations, cyclic nucleotide accumulation, and eicosanoid biosynthesis are currently interpreted as intracellular signals for protein kinase activation. Phosphorylation of multiple substrates by serine/threonine kinases C, A, and G or by tyrosine kinases directly coupled to receptors, is a final step in cell activation. Cross-talk between signal transduction pathways, along with the release of eicosanoids and cytokines acting as intercellular mediators, provides the potential for interactive regulation of glomerular cell functions.

Adenylyl Cyclases↗