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)

Certain endothelial receptors are coupled to a pertussis toxin-sensitive inhibitory guanine nucleotide-binding regulatory (Gi) protein. In pigs, hypercholesterolemia causes a selective impairment of this Gi protein-dependent pathway. Recent studies have suggested that hypercholesterolemia-induced endothelial dysfunction may be caused by lysophosphatidylcholine (LPC) derived from oxidized low-density lipoprotein (LDL). The aim of the present study was to determine whether LPC could inhibit the Gi protein-dependent pathway. Isolated rings of porcine coronary arteries were suspended for isometric tension recording in organ chambers filled with physiological salt solution (37 degrees C, 95% O2-5% CO2). In rings with endothelium contracted with prostaglandin F2 alpha, pertussis toxin (100 ng/ml) or LPC (10(-5) M) inhibited the endothelium-dependent relaxations evoked by UK-14,304, an alpha 2-adrenergic agonist, or by serotonin, but not those caused by bradykinin or ADP. LPC also did not inhibit relaxations produced by SIN 1, an endothelium-derived relaxing factor-nitric oxide donor. After treatment of the rings with pertussis toxin, LPC no longer inhibited the endothelium-dependent relaxations to serotonin. Although LPC inhibited the responses of membrane-bound receptors that activate the pertussis toxin-sensitive Gi protein, LPC did not affect the endothelium-dependent relaxations evoked by direct activation of the pertussis toxin-sensitive Gi protein by fluoride. These results suggest that LPC selectively inhibits a Gi protein-dependent pathway in porcine endothelial cells possibly by disrupting receptor-G protein interactions. LPC that is associated with oxidized LDL may mediate in part the dysfunction in the endothelial Gi protein-dependent pathway associated with hypercholesterolemia.
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PMID:Lysophosphatidylcholine modifies G protein-dependent signaling in porcine endothelial cells. 845 75

Experiments were designed to verify whether or not acute or chronic exposure to dexfenfluramine favors the occurrence of coronary vasospasm in vivo or in vitro. Rings of left anterior and left circumflex porcine coronary artery, with and without endothelium, were studied in conventional organ chambers for the measurement of isometric force. The donor pigs were divided into two groups: controls and animals fed for 4 weeks with dexfenfluramine. In each group, one-half of the animals underwent balloon denudation of the left anterior descending coronary artery at the beginning of the study. Coronary angiography was performed at the time of denudation and, in all animals, during the 3rd week of the study. Acutely, dexfenfluramine at concentrations higher than 10(-5) M caused contractions which were blunted by the presence of the endothelium and inhibited by indomethacin (an inhibitor of cyclooxygenase). Chronic treatment with dexfenfluramine did not affect coronary diameter and did not alter the response to intracoronary infusion of serotonin. Chronic treatment with dexfenfluramine reduced the contractions of rings without endothelium to serotonin, but not those to norepinephrine or endothelin. It did not affect endothelium-dependent relaxations in the absence or presence of pertussis toxin to serotonin, UK14304 (alpha-2 adrenergic agonist), adenosine diphosphate or aggregating platelets. Chronic treatment with dexfenfluramine did not modify relaxations of rings without endothelium to SIN-1 (nitric oxide donor; the active metabolite of molsidomine) or adenosine diphosphate. These findings do not support the hypothesis that acute or chronic exposure to dexfenfluramine favors the occurrence of coronary vasospasm.
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PMID:Acute and chronic effects of dexfenfluramine on the porcine coronary artery. 896 27

1. We examined the effect of endothelin-1 (ET-1) on basal and isoprenaline-enhanced L-type Ca2+ current (ICa,L) in guinea-pig ventricular myocytes under nystatin-perforated patch configuration. 2. ET-1 at concentrations of 1, 5 and 10 nM had little effect on basal ICa,L. However, ICa,L enhanced by isoprenaline (500 nM) was significantly attenuated by 5 nM ET-1 by more than 50%. This effect was reversed upon washout. ICa,L enhanced by forskolin was also decreased by ET-1. 3. The inhibitory effect of ET-1 against isoprenaline was completely blocked by the ETA receptor antagonist BQ-123 (1 microM). In myocytes incubated with pertussis toxin (PTX, 2 micrograms ml-1) for 5 h, ET-1 did not inhibit isoprenaline-enhanced ICa,L. 4. Although ET-1 has been shown to activate specific protein kinase C (PKC) isoforms, a significant inhibitory effect of ET-1 was maintained in the presence of the PKC inhibitor bisindolylmaleimide (20 nM). The nitric oxide (NO) donor SIN-1 (10 microM) attenuated but failed to prevent the ET-1 effect. 5. In summary, our results demonstrate that ET-1 is devoid of any significant effects on basal ICa,L. However, it exerts a potent inhibitory effect against isoprenaline-enhanced ICa,L. This effect is mediated through ETA receptors coupled to PTX-sensitive G-proteins and occurs in the presence of PKC inhibition and NO generation.
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PMID:Differential effects of endothelin-1 on basal and isoprenaline-enhanced Ca2+ current in guinea-pig ventricular myocytes. 928 74

1. The effect of diclofenac (10-100 microM) on vanadate-induced contraction of rat uterus in calcium-free buffer containing EDTA and the modification of this response by pertussis toxin (50 micrograms/ml), Rp-cAMPS (10 microM), W-7 (10 and 60 microM), L-NMMA (10 and 100 microM) and D-NMMA (100 microM) has been assessed. The effects of sodium nitroprusside (10 microM-1 mM), 3-morpholinosydnonimine (SIN-1; 0.1-100 microM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ; 0.1-100 microM) and 8-BrcGMP (10 microM to 1 mM) on vandate-evoked contraction were also studied. 2. Diclofenac produced dose-dependent relaxation of vanadate (0.3 mM)-induced contraction (EC50:17.3 +/- 1.8 microM, n = 11). This effect was significantly (P < 0.05) reduced by pertussis toxin (EC50: 37.4 +/- 4.5 microM, n = 6) and Rp-cAMPS (EC50:36.3 +/- 3.1 microM, n = 6). 3. The calmodulin inhibitor W-7 (1-100 microM) relaxed, in a concentration-dependent way, the vanadate contraction (EC50:67.0 +/- 18 microM). W-7 (10 and 60 microM) did not modify the relaxation elicited by diclofenac, which suggests that calmodulin inhibition and the increase of cAMP are two different actions of diclofenac. 4. The action of diclofenac was antagonized (P < 0.05) by L-NMMA (100 microM) and ODQ (1 and 100 microM) but not by D-NMMA (100 microM), which suggests the involvement of NO-synthase in this effect. 5. Sodium nitroprusside (1 mM) relaxed the vanadate contraction by only 31.7 +/- 1.04% (n = 7) and SIN-1 by 27.1 +/- 1.2% (n = 6). This suggests that, under the present experimental conditions, both NO donors were ineffective. However, 8-BrcGMP (EC50:327 +/- 71 microM, n = 7) relaxed this contraction up to 58.7 +/- 1.89%. Rp-cAMPS (10 microM) did not modify the 8-BrcGMP effect. Thus, a partial contribution of cGMP to inhibitor effect of drugs on rat uterus was possible. 6. The association between L-NMMA plus ODQ, L-NMMA plus Rp-cAMPS and ODQ plus Rp-cAMPS did not produce more displacement than L-NMMA, Rp-cAMPS or ODQ alone. This suggests the involvement of NO and cyclic nucleotides in the relaxant effect of diclofenac in rat uterus.
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PMID:Nitric oxide and cyclic nucleotides participate in the relaxation of diclofenac on rat uterine smooth muscle. 945 77

The cardiac L-type calcium current (I(Ca,L)) is an important regulator of myocardial contractility. It is activated by sympathetic stimulation and inhibited by parasympathetic activity via muscarinic acetylcholine receptors. Muscarinic inhibition of I(Ca,L) occurs via activation of pertussis toxin (PTX)-sensitive heterotrimeric G-proteins. Although recent studies have shown that expression of G(oalpha) is important for this effect in adult mouse ventricular cells, two other PTX-sensitive G-proteins (G(i2) and G(i3)) are also expressed in cardiocytes and are activated. Their role in the regulation of I(Ca,L) has not been examined. In addition, it is not known whether nodal/atrial cardiac cells use the same G-proteins. We show that gene inactivation of each of the three PTX-sensitive Galpha-proteins (alpha(i2), alpha(i3), and alpha(o)) affects muscarinic inhibition of cardiac I(Ca,L) in embryonic stem (ES) cell-derived cardiocytes. Inactivation of either alpha(i2) or alpha(i3) markedly slows the time course of muscarinic inhibition of I(Ca,L), and in cells where both alpha(i2) and alpha(i3) are inactivated the effects are not additive. We also establish an essential role for alpha(o)in this atrial/nodal-like cardiocyte system and show that alpha(o)acts proximal to NO generation. NO generation plays a critical role in I(Ca,L) regulation since the nitric oxide synthase (NOS) antagonist, l -NMMA, blocked the inhibition of I(Ca,L) in WT and in alpha(i2)/alpha(i3)-null cells. In WT cells, the NO generating agent SIN-1 inhibited I(Ca,L) and the addition of carbachol resulted in faster inhibition, suggesting that pathways in addition to NO are also activated. This study shows that alpha(i2) and alpha(i3) play a critical role in the normal inhibition of cardiocyte I(Ca,L). Thus, all muscarinic receptor activated G-proteins (G(i2), G(i3) and G(o)) are necessary for normal inhibition and act through both NO and non-NO signaling pathways.
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PMID:Galpha(i2), Galpha(i3)and Galpha(o) are all required for normal muscarinic inhibition of the cardiac calcium channels in nodal/atrial-like cultured cardiocytes. 1047 59

1. The role of the cGMP pathway in the modulation of the cardiac L-type Ca2+ current (ICa,L) by nitric oxide (NO) was examined in rat ventricular myocytes. 2. The NO donors DEANO, SIN-1, SNP, SNAP and GSNO had no significant effects on basal ICa,L. However, DEANO (100 microM) inhibited ICa,L after the current had been previously stimulated by either isoprenaline (Iso, 1-10 nM), a beta-adrenergic agonist, or isobutylmethyl-xanthine (IBMX, 10-80 microM), a wide spectrum phosphodiesterase (PDE) inhibitor. 3. The anti-adrenergic effect of DEANO on ICa,L was not mimicked by other NO donors (SIN-1, SNAP and SPNO). 4. The NO-sensitive guanylyl cyclase inhibitor ODQ (10 microM), antagonized the inhibitory effect of DEANO on ICa,L. Likewise, inhibitors of the cGMP-dependent protein kinase (cG-PK), Rp-8-chloro-phenylthio-cGMP (10 microM) and KT5823 (0.1 and 0.3 microM), also abolished the inhibitory effect of DEANO on Iso (1-10 nM)-stimulated ICa,L. 5. Intracellular dialysis with exogenous cAMP (10-100 microM) blunted the inhibitory effect of DEANO (10 and 100 microM) on ICa,L. SNAP and SNP also had no effect on the cAMP-stimulated ICa,L. 6. Pre-treatment of the myocytes with pertussis toxin (0.5 microg ml-1, 4-6 h at 37 degrees C) eliminated the inhibitory effect of DEANO (100 microM) on ICa,L, in the presence of either Iso (0.01 and 1 nM) or IBMX (10-80 microM). 7. These results demonstrate that DEANO produces anti-adrenergic effects in rat ventricular myocytes. This effect of DEANO occurs in a cGMP-dependent manner, and involves activation of cG-PK and regulation of a pertussis toxin-sensitive G protein.
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PMID:G protein-mediated inhibitory effect of a nitric oxide donor on the L-type Ca2+ current in rat ventricular myocytes. 1117 96

Opiates, such as morphine, have been used extensively in the clinical management of pain due to their potent analgesic effect. Astrocytes, representing a major non-neuronal cell population in the CNS, contain opioid receptors that are actively involved in several brain functions. This study was designed to evaluate the effects by which morphine, a preferential mu-opioid receptor agonist, contributes to cytotoxicity of nitric oxide (NO) species, including NO and peroxynitrite (ONOO-), in primary rat neonatal astrocytes. Primary astrocytes isolated from the cerebral cortex of 1- to 2-day-old Sprague-Dawley rats were treated with morphine, naloxone, and 3-morpholinosydnonimine (SIN-1), a donor of peroxynitrite. Morphine significantly protected primary rat astrocytes from apoptosis mediated by sodium nitroprusside, an NO donor, and SIN-1 in a dose-dependent manner, whereas it did not in other types of cells including C6 glioma, RAW 264.7, and HL-60 cells. Moreover, naloxone antagonized the protective effects of morphine on SIN-1-induced apoptosis. Morphine also inhibited the nuclear condensation and fragmentation of SIN-1-treated cells that was antagonized by naloxone pretreatment. The protective role of morphine in SIN-1-induced apoptosis was dependent on an intracellular antioxidant system such as GSH. Furthermore, the effects of morphine on SIN-1-induced cytotoxicity were prohibited by pretreatment with the G(i) protein inhibitor, pertussis toxin, and the phosphatidylinositol 3-kinase (PI3 kinase) inhibitors, wortmannin and LY294002. Taken together, these results suggest that morphine may protect primary rat astrocytes from apoptosis by NO species via the signaling cascades that involve both G protein and PI3 kinase.
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PMID:Protective effects of morphine in peroxynitrite-induced apoptosis of primary rat neonatal astrocytes: potential involvement of G protein and phosphatidylinositol 3-kinase (PI3 kinase). 1127 62

We have previously reported that, depending on the dose, nitric oxide (NO)-generating agents exert a dual facilitatory and inhibitory action on glutamatergic transmission on the rostral ventrolateral medulla (RVLM) neurons. The molecular mechanisms underlying the NO-mediated synaptic inhibition have not yet been defined. Here we show that the amplitude of excitatory postsynaptic currents (EPSCs) was reversibly reduced by the NO donors 3-morpholinylsydnoneimine (SIN-1) (1 mM) and spermine NONOate (1 mM). This effect was antagonized by an active peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride, G(i/o)-coupled receptor blockers, N-ethylmaleimide and pertussis toxin, A(1) adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, or adenosine deaminase. However, NO-sensitive guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), or cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) had no effect on the inhibitory action of SIN-1 on EPSCs. Perfusion of adenosine mimicked and subsequently occluded the action of SIN-1. Inhibition of EPSC amplitude by SIN-1 was associated with an increase in the paired-pulse ratio of EPSCs. Furthermore, SIN reduced the frequency of spontaneous EPSCs without altering their amplitude of distribution. Pretreatment with N-type Ca(2+)-channel blocker omega-conotoxin GVIA selectively blocked SIN-1-induced inhibition of EPSCs. These results suggest that a higher dose of SIN-1 acts presynaptically to elicit a synaptic depression on the RVLM neurons through an inhibition of presynaptic N-type Ca(2+)-channel activity, leading to reduced glutamate release. The presynaptic action of SIN-1 is mediated by the formation of peroxynitrite, which subsequently acts to release adenosine to activate A(1) adenosine receptors.
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PMID:3-Morpholinylsydnonimine inhibits glutamatergic transmission in rat rostral ventrolateral medulla via peroxynitrite formation and adenosine release. 1532 40

We investigated the effects of hydrogen peroxide (H2O2) on relaxation of the cat lower esophageal sphincter (LES). Vasoactive intestinal peptide (VIP) caused dose-dependent relaxation of LES, and H2O2 reduced VIP-induced relaxation. Relaxation was also attenuated by pertussis toxin (PTX), indicating a Gi/o component. VIP treatment increased [35S]GTPgammaS binding to Gs and Gi3 protein, but not to Go, Gq, Gil or Gi2. This increase in Gs or Gi3 binding was reduced by H2O2. However, the relaxation induced by sodium nitroprusside (SNP), 3-morpholino sydnomine (SIN-1), 8-br cGMP (cGMP analog), forskolin (adenylate cyclase activator), and dibutyryl-cAMP (a stable cAMP analog) was not reduced by H2O2. These data suggest that H202 inhibits VIP-induced relaxation via a Gi-dependent pathway, perhaps by inhibiting the activation of G(i3) or Gs downstream of the VIP receptor and independent of cAMP or NO-cGMP signaling.
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PMID:Effect of hydrogen peroxide on VIP-induced relaxation of the cat lower esophageal sphincter. 1808 10

Under physiological conditions, hypochlorous acid (HOCl) is the major product of myeloperoxidase, a ferric heme enzyme released in inflammatory diseases. In the present study, we investigated the effect of HOCl compared to hydrogen peroxide (H2O2) on the vasoactive intestinal polypeptide (VIP)-induced relaxation of feline lower esophageal sphincter (LES) strips. Isometric tension on LES strips was measured using a force transducer. VIP induced the relaxation of basal LES tone in a concentration-dependent manner. Pretreatment with HOCl (10(-4) M) significantly reduced the VIP-induced relaxation at smaller concentrations than H2O2 (10(-3) M). VIP-induced relaxation is mediated via the Gi/o protein, since pretreatment with Pertussis Toxin (PTX) showed an inhibitory effect on the relaxation. HOCl showed an additional inhibitory effect on the reduced relaxation by PTX, indicating that HOCl might affect another G protein as well as Gi/o. However, HOCl did not affect SNP-, SIN-1-, and 8-br-cGMP-induced relaxation. Nor did HOCl modify the relaxation induced by either forskolin or db-cAMP in LES muscle strips. These results suggest that during short-term treatment, HOCl may damage the upstream events including G protein level, and result in alteration of LES tone in the feline esophagus, similar to the inhibitory effects of H2O2.
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PMID:Inhibitory effect of hypochlorous acid on lower esophageal sphincter tone relaxation by vasoactive intestinal peptide. 1909 23


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