Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the effects of various beta-adrenoceptor (beta AR) antagonists and local anesthetics (LAs), i.e. substances possessing one basic and one lipophilic domain each, on activation of regulatory heterotrimeric guanine nucleotide-binding proteins (G-proteins). In membranes of differentiated HL-60 cells, propranolol activated high-affinity GTP hydrolysis with a half-maximal effect at 0.19 mM and a maximum at 1 mM. There was a close correlation between the log Q values (logarithm of the octanol: water partition coefficient) of beta AR antagonists and the logarithm of their effectiveness at activating GTPase (EC 3.6.1.-) in HL-60 membranes. The lipophilic LA, tetracaine, was also an effective activator of GTPase in HL-60 membranes, whereas more hydrophilic LAs were less stimulatory (bupivacaine and lidocaine) or even inhibitory (procaine). Propranolol and tetracaine also stimulated binding of guanosine 5'-O-[3-thio]triphosphate (GTP[gamma S]) to HL-60 membranes, but their stimulatory effects on GTP[gamma S] binding were smaller than on GTP hydrolysis. The stimulatory effects of propranolol and tetracaine on GTPase and GTP[gamma S] binding were inhibited by pertussis toxin. Propranolol and tetracaine effectively activated GTP hydrolysis of a reconstituted mixture of bovine brain Gi/Go-proteins, but the concentrations of substances needed for GTPase activation were higher than in HL-60 membranes. Procaine showed stimulatory effects on the GTPase of Gi/Go-proteins. Our data show that beta AR antagonists and LAs activate pertussis toxin-sensitive G-proteins, presumably through interaction with the C-terminus of their alpha-subunits. Apparently, the lipophilic domain of beta AR antagonists and LAs is more important for G-protein activation than the basic domain. We discuss the possibility that activation of nucleoside diphosphate kinase by beta AR antagonists and LAs contributes to their stimulatory effects on GTP hydrolysis in HL-60 membranes.
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PMID:Lipophilic beta-adrenoceptor antagonists and local anesthetics are effective direct activators of G-proteins. 791 2

Left atria were isolated from rats made hypothyroid by adding propylthiouracil to their drinking water, such rats after saturating doses of thyroid hormones, and from control rats. Isoproterenol (ISO; 1 microM) increased the values of developed tension (DT), maximal rate of tension development (+dt/dt) and tension fall (-dT/dt). The effect was largest in hypothyroid and lowest in hyperthyroid atria. The adenosine A1-receptor agonist N6-(phenylisopropyl)-adenosine (PIA) had a powerful negative inotropic effect in ISO-stimulated atria. The effects of PIA on +dT/dt, -dT/dt and DT were enhanced in hypothyroidism. Adenosine receptor number was not decreased. The amount of total Gi-like proteins was estimated by pertussis toxin labeling. The amounts of Gi2 and Gi3 were estimated in Western blots using such antisera raised in rabbits against peptides corresponding to parts of their sequences, using purified recombinant alpha subunits as standards. The amounts of low and high molecular weight forms of Gs were estimated by cholera toxin labeling Gi2, Gi3 and pertussis toxin substrate concentrations were slightly lower in the hypothyroid animals, while the amounts of both forms of Gs per mg of protein were only half of those in euthyroid rat atria. The levels of Gi2 and Gi3 were greatly elevated as compared to Gs as membrane marker. These changes were reversed by treatment of the hypothyroid rats with thyroid hormones. In conclusion, the present results show an enhanced negative inotropic effect of an adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhanced negative inotropic effect of an adenosine A1-receptor agonist in rat left atria in hypothyroidism. 791 34

In rabbit renal cortical collecting tubule (CCT), perfused in vitro at 38 degrees C, ATP in concentrations of 10(-7) M and greater inhibits arginine vasopressin (AVP)-stimulated osmotic water permeability (Pf). The P1-purinergic receptor antagonist 8-phenyltheophylline did not attenuate the inhibitory action of ATP, and the poorly hydrolyzable ATP analogue, 5'-adenylylimidodiphosphate (AMP-PNP), mimicked the effect of ATP, arguing against an effect of ATP on a P1 receptor or the "P site." Purinergic receptor agonists inhibited AVP-stimulated Pf with the following rank order efficacy: ATP = ADP = UTP = AMP-PNP = alpha, beta-methylene-ATP > 2-methylthio-ATP >> AMP > adenosine, consistent with the pharmacology of a "nucleotide" receptor subtype. Pertussis toxin pretreatment attenuated the action of 10(-5) and 10(-6) MATP; however, 10(-4) MATP failed to inhibit the hydrosmotic action of forskolin or 8-bromoadenosine 3',5'-cyclic monophosphate. Pretreatment with the phosphodiesterase inhibitor RO20-1724 or indomethacin did not inhibit the action of ATP. Staurosporin and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester significantly attenuated the inhibition of Pf by lower concentrations of ATP. These data suggest that ATP activates nucleotide receptors on the CCT, mobilizing intracellular Ca2+, which inhibits the hydrosmotic action of AVP.
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PMID:ATP inhibits the hydrosmotic effect of AVP in rabbit CCT: evidence for a nucleotide P2u receptor. 806 90

We studied the survival of Bordetella pertussis in four suspending solutions (Casamino Acids broth, deionized water, phosphate-buffered saline, and serum inositol), subjected to three storage temperatures (4, -20, and -70 degrees C) and two freezing methods (direct freezing and fast-freezing in an ethanol-dry-ice bath). Recovery rates were higher for longer periods for suspensions stored at -70 degrees C than those stored at -20 or 4 degrees C. Serum inositol showed the highest recovery rates for all experimental conditions, followed by Casamino Acids, deionized water, and phosphate-buffered saline. Cell viability was significantly reduced in phosphate-buffered saline suspensions fast-frozen before storage. These results identify optimal conditions for storing B. pertussis cells and are applicable to the collection, transport, and storage of aspirated nasopharyngeal samples for use in the laboratory diagnosis of pertussis.
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PMID:Viability of Bordetella pertussis in four suspending solutions at three temperatures. 807 2

Pertussis toxin is a member of ADP-ribosylating bacterial toxins that are capable of catalyzing the cleavage of the N-glycosidic bond of NAD+ and the transfer of its ADP-ribose moiety to G proteins. The catalytic S1 subunit of pertussis toxin uses signal transducing G proteins as acceptor substrates but can also catalyze the transfer of the ADP-ribose moiety to water in the absence of G proteins. Site-directed mutagenesis followed by kinetic analyses of truncated soluble mutant proteins revealed that His-35 of S1 is a catalytic residue because alterations of this residue affect the turnover rate of NAD-glycohydrolysis by approximately two orders of magnitude without significantly affecting substrate binding. Replacement of the imidazole of His-35 by the side chain of glutamine maintained the highest residual activity. The pH dependence of the enzyme activity showed only slight variations over the experimental range with an optimum at pH 7.5 and an approximate pKa of 6.5 to 7. This pH dependence was abolished by the Gln substitution, which still retained significant activity, suggesting that His-35 probably does not act as a true base but rather as a proton acceptor. Direct catalytic roles for several other residues were ruled out. Ser-52 substitutions resulted in slight alterations of both kcat and Km for NAD+ suggesting an involvement in maintaining the local geometry of the active site rather than a direct role in catalysis for this residue. Kinetic studies on mutants with substitutions of Ser-40 indicate a role in NAD+ binding for this residue. In conjunction with previous findings, these studies suggest that the NAD-glycohydrolase activity of S1 utilizes 2 catalytic residues, His-35 and the previously identified Glu-129. The enzyme mechanism could therefore proceed through an activation by polarization of the acceptor substrate water or G protein by His-35, and the stabilization of an oxocarbonium-like transition state intermediate by Glu-129.
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PMID:The NAD-glycohydrolase activity of the pertussis toxin S1 subunit. Involvement of the catalytic HIS-35 residue. 811 96

Despite improvements in infant mortality, 500,000 infants die every year in the Americas. In Costa Rica, child mortality dropped from 68/1000 live births in 1970 to 20/1000 in 1980 as a result of improved hygiene and nutrition, immunization, and treatment. In most other countries of the Americas, infant mortality rates have declined substantially mainly because of public health programs. Educational levels of mothers and per capita national product also exert a notable influence on infant mortality. Poverty inflicts health problems: 177 million children are malnourished, and 40% of children in developing countries are undernourished, a state of affairs responsible for almost 60% of infant deaths. Breast-feeding plays a vital role in the first year of life by providing high quality nutrition and immunological protection, and emotional bonding between the mother and the child. Unfortunately, breast-feeding prevalence and duration is on the decline in developing countries. Safe drinking water and good sanitation are crucial in preventing and reducing child mortality. Women who become pregnant at either extreme of the reproductive age are exposed to higher maternal and pediatric risks; so are multiparous women, and women with short birth intervals. Most child deaths between the ages of 1-4 are preventable by health intervention: the main causes are diarrheal and respiratory diseases, malnutrition, and vaccine-preventable infectious diseases. Intestinal infections cause almost 5 million child deaths a year, and oral rehydration therapy is the most effective preventive measure. Vaccination is the most effective means of preventing measles, polio, tetanus, diphtheria, tuberculosis, and pertussis. In many countries, malaria has resurfaced with some 250-300 million new cases every year. Children and pregnant women are especially vulnerable to suffer serious complications. There were a quarter million cases of cholera in the Americas between early 1991 and August, 1992. AIDS is also a threat to child health because of the rising numbers of infected mothers and pregnant women.
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PMID:Children's health in the developing world: much remains to be done. 814 86

We examined the effects of adenosine and adenosine analogues on arginine vasopressin (AVP)-induced increases in osmotic water permeability (Pf; micron/s) and adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in rat inner medullary collecting ducts (IMCDs). When added to the bath, the A1 receptor agonist N6-cyclohexyladenosine (CHA) produced a rapid and reversible inhibition of AVP-stimulated (10 pM) Pf (1,781 +/- 195 to 314 +/- 85 microns/s at 0.3 microM CHA; n = 9). The inhibitory effect of CHA was concentration dependent, with a 50% inhibitory concentration of 10 nM. The effect of CHA was inhibited by prior exposure of IMCDs to the A1 receptor antagonist 1,3-dipropylxanthine-8-cyclopentylxanthine (DP-CPX; 1 microM) or by preincubation with pertussis toxin. CHA had no effect on cAMP-induced increases in Pf. In addition to CHA, adenosine and the nonselective agonist 5'-(N-ethylcarboxamido)-adenosine (NECA) inhibited AVP-dependent Pf by > or = 70%, whereas the A2 receptor agonist CGS-21680 had no effect. Luminal adenosine (0.1 mM) had no effect on basal or AVP-stimulated Pf. CHA, NECA, and adenosine but not CGS-21680 inhibited AVP-stimulated cAMP accumulation in a concentration-dependent manner (50% inhibitory concentrations 0.1-300 nM). The inhibitory effect of CHA on AVP-stimulated cAMP accumulation was attenuated by DPCPX. We conclude that adenosine, acting at the basolateral membrane, inhibits AVP action in the IMCD via interaction with A1 receptors. The inhibition occurs proximal to cAMP generation and likely involves an inhibitory G protein.
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PMID:Adenosine A1 receptor-mediated inhibition of vasopressin action in inner medullary collecting duct. 820 63

Prostaglandin E2 (PGE2) modulates both water and sodium transport in the rabbit cortical collecting duct (CCD). To determine whether these effects are mediated by separate PGE2 receptors, we compared the effects of PGE2 and its analogue sulprostone in the isolated perfused rabbit CCD. PGE2 increased basal water permeability (hydraulic conductivity), whereas sulprostone did not. PGE2 and sulprostone were equipotent inhibitors of water absorption when it was prestimulated by vasopressin. Pertussis toxin completely reversed the inhibitory effect of sulprostone but only partially reversed the inhibitory effect of PGE2. In contrast, a protein kinase C (PKC) inhibitor, staurosporine, partially reversed the inhibitory effect of PGE2 but had no effect on sulprostone. PGE2 also raised intracellular calcium ([Ca2+]i). This effect is coupled to its capacity to inhibit Na+ absorption. Sulprostone was 10-fold less potent than PGE2 both in raising [Ca2+]i or inhibiting sodium transport. The results suggest sulprostone selectively interacts with a PGE2 receptor coupled to pertussis toxin-sensitive inhibition of water permeability. Sulprostone less potently activates a PGE2 receptor coupled to [Ca2+]i, PKC activation, and sodium transport and completely fails to interact with the PGE2 receptor that stimulates water permeability in the collecting duct. These results suggest distinct PGE2 receptors modulate sodium and water transport in the CCD.
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PMID:Evidence that separate PGE2 receptors modulate water and sodium transport in rabbit cortical collecting duct. 823 44

Linomide (LS-2616, quinoline-3-carboxamide) is a synthetic immunomodulator that stimulates natural killer cell activity and activates several lymphocytic subpopulations in experimental animals and humans. In this study we determined the effect of oral treatment with linomide on the development of experimental autoimmune encephalomyelitis, an animal model for immune-mediated human demyelinating disorders. Experimental autoimmune encephalomyelitis was induced in SJL/J mice and in an outbred strain of rats (Sabra) by subcutaneous injection of spinal cord homogenate in adjuvant followed by inoculation with Bordetella pertussis. Linomide was administered in drinking water, at an estimated dose of 50 to 100 mg/kg/day. None of the linomide-treated mice (0/41) and Sabra rats (0/15) developed any clinical or pathological signs of experimental autoimmune encephalomyelitis, whereas almost all control animals (48/53 and 18/19, respectively) were severely paralyzed and 64.5% died from the disease. Lymphocytes obtained from linomide-treated animals had reduced in vitro proliferative responses to guinea pig myelin basic protein, proteolipid protein of the myelin, and tuberculin-purified protein derivative, unlike antigen-independent proliferation which was rather unaffected. Natural killer cell activity (tested by a cytotoxic assay on radiolabeled YAC-1 target cells) was significantly enhanced in mice treated with linomide. Our results indicate that modulation of the immune system with linomide leads to complete inhibition of experimental autoimmune encephalomyelitis in the absence of systemic immunosuppression. Linomide could therefore be of use in future clinical trials for the treatment of human autoimmune demyelinating disorders.
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PMID:Inhibition of acute, experimental autoimmune encephalomyelitis by the synthetic immunomodulator linomide. 823 57

Mice were immunized with whole killed blood stage Plasmodium yoelii parasites in 15 adjuvant formulations then boosted and challenged with parasitized blood. Five of six groups immunized with the Ag in oil-in-water emulsions or formulations without oil were protected. Formulations that induced protection contained saponin, pertussis, copolymer P1004, and detoxified RaLPS. In contrast, none of nine groups of animals immunized with Ag in water-in-oil emulsions were protected. Ineffective adjuvants included CFA and water-in-squalene emulsions with copolymer L141 plus detoxified RaLPS, dimethyldioctadecyl ammonium bromide, and mycobacterial cell wall skeletons. Antibody was measured by ELISA against disrupted parasites and by indirect fluorescent antibody (immunofluorescence) using intact parasites. Protection was associated with antibody of the IgG2a isotype detected by immunofluorescence but not with other isotypes detected by immunofluorescence or any type antibody detected by ELISA. The water-in-oil adjuvants induced high titers by ELISA but low titers by immunofluorescence. These results, together with Western blot analyses, suggested that adjuvant vehicles control the specificity of antibody and that this, in turn, is essential for induction of protective immune responses in this model.
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PMID:Role of adjuvants in the modulation of antibody isotype, specificity, and induction of protection by whole blood-stage Plasmodium yoelii vaccines. 825 12


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