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)

Intracellular free Ca++ concentration ([Ca++]i) was monitored using the fluorescence from the dye fura-2-acetoxymethylester in single myocytes from rat portal vein. In the presence of oxodipine (a L-type Ca++ channel inhibitor), norepinephrine (10 microM) evoked transient increases in [Ca++]i which were related to release of Ca++ from intracellular stores. The alpha-1 adrenoceptors mediating intracellular Ca++ release and inositol phosphate accumulation were identified by using subtype-selective agonists and antagonists. Pretreatment with chloroethylclonidine had little effect on the norepinephrine-induced increase in [Ca++]i and inositol phosphate accumulation. In contrast, prazosin, 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane and alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy)ethyl)-amino )- propyl)benzeneacetonitrile fumarate produced a concentration-dependent inhibition of both intracellular Ca++ release and inositol phosphate accumulation. The rank of potency was prazosin > 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane > alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy)ethyl)-amino - propyl) benzeneacetonitrile fumarate. Methoxamine was as effective as norepinephrine but was less potent as shown by the rightward shift of the concentration-response curves. These results indicate that myocytes from rat portal vein express alpha-1A adrenoceptors whose activation stimulates phosphoinositide turnover and release of Ca++ from intracellular stores. The alpha-1A adrenoceptor stimulation of [Ca++]i and subsequent activation of Ca(++)-activated Cl- current was insensitive to intracellular applications of pertussis toxin, but concentration-dependently blocked by intracellular dialysis with a pipette solution containing anti-alpha q/alpha 11 antibody (whole cell recording mode).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Activation of alpha-1A adrenoceptors mobilizes calcium from the intracellular stores in myocytes from rat portal vein. 790 27

Noradrenaline stimulates not only Ca2+ mobilization but also cAMP formation through activation of alpha 1-adrenoceptors in hepatocytes from mature male rats. We examined which subtype(s) of alpha 1-adrenoceptor mediate these signal transduction mechanisms. Treatment of hepatocytes with chloroethylclonidine produced a dose-dependent inhibition of noradrenaline-induced Ca2+ mobilization, involving both transient and sustained components. Chloroethylclonidine also blocked noradrenaline-induced cAMP accumulation. It was observed that prazosin was much more potent than WB4101 (2-(2,6-dimethoxy-phenoxyethyl)aminomethyl-1,4-benzodioxane) in antagonizing noradrenaline-induced Ca2+ mobilization. The same potency order was found in cAMP formation studies. Pretreatment of rats with pertussis toxin did not affect alpha 1-adrenergic responsiveness. Incubations of hepatocytes with tumor-promoting phorbol esters eliminated both Ca2+ mobilization and cAMP accumulation caused by noradrenaline. Our data suggest that in hepatocytes from mature male rats, single alpha 1B-adrenoceptors are linked to cAMP formation as well as Ca2+ mobilization.
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PMID:Alpha 1B-adrenoceptor-mediated stimulation of Ca2+ mobilization and cAMP accumulation in isolated rat hepatocytes. 810 51

Somatostatin (SRIF) induces its biological actions by interacting with a family of five recently cloned receptors. SRIF receptor subtype, SSTR1, has high affinity for SRIF, but no ligand has been available that selectively binds to this receptor. Desamino acid(1,2,5) [DTryptophan8, N-p-isopropl-4-aminomethyl-l-phenylalanine9]SRIF(des-AA1,2,5 [DT rp8, IAmp9]SRIF inhibits the binding of [125ITyr11]SRIF to the cloned human SSTR1 with an affinity of 1.8+0.7nM, but does not bind to the other cloned SRIF receptors. des-AA1,5[125ITyr2,DTrp8,IAmp9]SRIF bound selectively, potently and saturably to SSTR1 with a Kd of 0.5 + 0.1 nM and a maximal binding density of 226 +/- 56 fmol/mg of protein. The binding of des-AA1,5[125ITyr2,DTrp8,IAmp9]SRIF to SSTR1 was potently inhibited by SRIF, [DTrp8]SRIF, des-AA1,2,5[DTrp8,IAmp9,DSer13]SRIF and SRIF 28 with K, values of 0.7+0.3, 0.2+0.2, 4.3+0.7 and 0.6+0.1 nM, respectively. SRIF analogs that selectively bind to SSTR2 and SSTR5 were impotent in displacing des-AA1,5[125ITyr2,DTrp8,IAmp9]SRIF from human SSTR1. des-AA1,5[125ITyr2,DTrp8,IAmp9]SRIF binding to SSTR1 expressed in COS-7 cells was reduced by GTPgS, and this effect was prevented by pertussis toxin treatment. In contrast, the binding of[125ITyr11]SRIF to SSTR1 was not affected by these treatments. These findings indicate that des-AA1,5[125ITyr2,DTrp8,IAmp9]SRIF may bind to SSTR1 in a defferent manner than SRIF. des-AA1,2,5[DTrp8,IAmp9]SRIF and its tyrosine analog are the first ligands that selectively bind to SSTR1 with high affinity and should be useful in localizing and determining the functional properties of this receptor.
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PMID:Development of a selective agonist at the somatostatin receptor subtype sstr1. 878 39

The objective of this study was to characterize the plasmin-induced stimulation of leukotriene (LT) B4 biosynthesis in human peripheral monocytes (PM). Plasmin up to 175 x 10(-3) CTA U/ml triggers a concentration-dependent release of 5-lipoxygenase-derived LTB4 while release of the cyclooxygenase products thromboxane (TX) B2 and prostaglandin (PG) E2 remained unaffected. The stimulatory effect appeared to be specific in as much as 1) it was found in PM, but not in polymorphonuclear neutrophils (PMN), 2) it requires the lysine binding sites of plasmin molecule since it was inhibited by the lysine analogues 6-aminohexanoic acid (6-AHA) and trans-4(aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA), 3) the intact catalytic center of plasmin is required since neither plasminogen nor catalytic center-blocked plasmin share the stimulatory effect of active plasmin, 4) other serine proteases such as alpha-chymotrypsin, human neutrophil elastase and cathepsin G did not stimulate release of detectable amounts of LTB4 from PM. In addition, catalytic center-blocked plasmin antagonized the stimulatory effect of active plasmin. Plasmin-mediated monocyte activation apparently proceeds via a pertussis toxin-sensitive G protein. Plasmin did not increase inositol (1,4,5) trisphosphate levels, but a time- and concentration-dependent stimulation of cyclic GMP formation was observed. The data show that plasmin is a specific stimulus for human peripheral monocytes. Plasmin may be an important link between the coagulation cascade and inflammatory reactions.
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PMID:Plasmin is a specific stimulus of the 5-lipoxygenase pathway of human peripheral monocytes. 890 97

We have previously reported that the serine protease plasmin generated during contact activation of human plasma triggers biosynthesis of leukotrienes (LTs) in human peripheral monocytes (PMs), but not in polymorphonuclear neutrophils (PMNs). We now show that purified plasmin acts as a potent chemoattractant on human monocytes, but not on PMNs. Human plasmin or plasminogen activated with urokinase, but not active site-blocked plasmin or plasminogen, elicited monocyte migration across polycarbonate membranes. Similarly, stimulation of monocytes with plasmin, but not with active site-blocked plasmin or plasminogen, induced actin polymerization. As assessed by checkerboard analysis, the plasmin-mediated monocyte locomotion was a true chemotaxis. The plasmin-induced chemotactic response was inhibited by the lysine analog trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA), which prevents binding of plasmin/ogen to the appropriate membrane binding sites. In addition, active site-blocked plasmin inhibited monocyte migration triggered by active plasmin. Further, plasmin-induced monocyte chemotaxis was inhibited by pertussis toxin (PTX) and 1-O-hexadecyl-2-O-methyl-rac-glycerol (HMG) and chelerythrine, two structurally unrelated inhibitors of protein kinase C (PKC). Plasmin, but not active site-blocked plasmin or plasminogen, triggered formation of cyclic guanosine monophosphate (cGMP) in monocytes. LY83583, an inhibitor of soluble guanylyl cyclase, inhibited both plasmin-induced cGMP formation and the chemotactic response. The latter effect could be antagonized by 8-bromo-cGMP. In addition, KT5823 and (Rp)-8-(p-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate [(Rp)-8-pCPT-cGMPs], two structurally unrelated inhibitors of cGMP-dependent protein kinase, inhibited plasmin-mediated monocyte chemotaxis. Thus, beyond being a stimulus for lipid mediator release, plasmin is a potent and specific chemoattractant for human monocytes acting via a cGMP-dependent mechanism. Therefore, plasmin represents a proinflammatory activator for human monocytes.
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PMID:Plasmin is a potent and specific chemoattractant for human peripheral monocytes acting via a cyclic guanosine monophosphate-dependent pathway. 919 82

The alpha2-adrenoceptor mediating inhibition of forskolin-stimulated cyclic AMP accumulation in human neuroblastoma SH-SY5Y cells was further characterized. The alpha2-adrenoceptor agonists, UK 14,304 (5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline), oxymetazoline, guanfacine, (-)-noradrenaline and clonidine concentration-dependently decreased cyclic AMP accumulation in this cell line (Emax ca. 50% inhibition). Agonist pEC50 values ranged between 6.7 and 7.8. Clonidine was a partial agonist. The effects of UK 14,304 were blocked after a pertussis toxin treatment. The concentration-response curves of UK 14,304 were shifted to the right in a parallel manner by the following antagonists (mean pK(B) values): yohimbine (8.17), idazoxan (7.63), prazosin (6.66), 2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2 H,4H) isoquinolindione (ARC 239; 7.12) and 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB-4101; 8.12). The relatively high pKB values of prazosin and ARC 239 point to a non-alpha2A-adrenoceptor-mediated effect. The relatively high pK(B) value of WB-4101 further characterizes the alpha2-adrenoceptor in SH-SY5Y cells as being of the alpha2C subtype. The analysis of the expression of alpha2-adrenoceptor subtypes by reverse transcriptase-polymerase chain reaction (RT-PCR) revealed the exclusive presence of alpha2C-adrenoceptor mRNA in SH-SY5Y cells. We propose that inhibition of forskolin-stimulated cAMP accumulation in SH-SY5Y cells be used as a functional model of human, native alpha2C-adrenoceptors.
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PMID:Functional alpha2C-adrenoceptors in human neuroblastoma SH-SY5Y cells. 1037 21

In rat left ventricular papillary muscle, phenylephrine, an alpha1-adrenoceptor agonist, induced a triphasic inotropic response; an initial transient, small, positive inotropic effect followed by a transient chloroethylclonidine-sensitive negative inotropic effect and a sustained 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB4101)-sensitive positive inotropic effect. Treatment with pertussis toxin for 2 days significantly inhibited only the transient negative inotropic effect without changing the sustained positive inotropic effect. This treatment also prevented the acetylcholine (1 microM)-induced negative inotropic effect. Further, phenylephrine-induced transient negative inotropic effect was attenuated in the presence of ouabain. These results suggest that pertussis toxin-sensitive or -insensitive G-protein may be responsible for alpha1-adrenoceptor subtype-mediated negative inotropic effect or positive inotropic effect, respectively, in which the transient negative inotropic effect was produced via the stimulation of Na+, K+ pump, presumably through pertussis toxin-sensitive G-protein-dependent pathway.
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PMID:Pertussis toxin-sensitive and -insensitive mechanisms of alpha1-adrenoceptor-mediated inotropic responses in rat heart. 1142 48

Activation of G protein-coupled alpha(2) adrenergic receptors (ARs) inhibits epileptiform activity in the hippocampal CA3 region. The specific mechanism underlying this action is unclear. This study investigated which subtype(s) of alpha(2)ARs and G proteins (Galpha(o) or Galpha(i)) are involved in this response using recordings of mouse hippocampal CA3 epileptiform bursts. Application of epinephrine (EPI) or norepinephrine (NE) reduced the frequency of bursts in a concentration-dependent manner: (-)EPI > (-)NE >>> (+)NE. To identify the alpha(2)AR subtype involved, equilibrium dissociation constants (pK(b)) were determined for the selective alphaAR antagonists atipamezole (8.79), rauwolscine (7.75), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride (WB-4101; 6.87), and prazosin (5.71). Calculated pK(b) values correlated best with affinities determined previously for the mouse alpha(2A)AR subtype (r = 0.98, slope = 1.07). Furthermore, the inhibitory effects of EPI were lost in hippocampal slices from alpha(2A)AR-but not alpha(2C)AR-knockout mice. Pretreatment with pertussis toxin also reduced the EPI-mediated inhibition of epileptiform bursts. Finally, using knock-in mice with point mutations that disrupt regulator of G protein signaling (RGS) binding to Galpha subunits to enhance signaling by that G protein, the EPI-mediated inhibition of bursts was significantly more potent in slices from RGS-insensitive Galpha(o)(G184S) heterozygous (Galpha(o)+/GS) mice compared with either Galpha(i2)(G184S) heterozygous (Galpha(i2)+/GS) or control mice (EC(50) = 2.5 versus 19 and 23 nM, respectively). Together, these findings indicate that the inhibitory effect of EPI on hippocampal CA3 epileptiform activity uses an alpha(2A)AR/Galpha(o) protein-mediated pathway under strong inhibitory control by RGS proteins. This suggests a possible role for RGS inhibitors or selective alpha(2A)AR agonists as a novel antiepileptic drug therapy.
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PMID:Regulator of G protein signaling protein suppression of Galphao protein-mediated alpha2A adrenergic receptor inhibition of mouse hippocampal CA3 epileptiform activity. 1922 79