UMLS:C0043167 - FACTA Search

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

The aim of the present study was to clarify the cellular mechanisms underlying the alpha(2)-adrenoceptor-mediated contraction of porcine myometrium (nonvascular smooth muscle). Acetylcholine (3 nM-1 microM), clonidine (1 nM-10 microM) and 5-bromo-N-[2-imidazolin-2-yl]-6-quinoxalinamine (UK14304) (1 nM-10 microM) in Krebs solution caused a concentration-dependent contraction in the longitudinal muscles of the porcine uterus with similar EC(50) values and maximum responses. A lowered external Ca(2+) concentration and verapamil (10 nM-10 microM) decreased the contractile response to clonidine and UK14304 more markedly than the response to acetylcholine. However, in Kumagai solution, neither clonidine nor UK14304 caused contractile responses, but acetylcholine remained effective. The effects of alpha(2)-adrenoceptor agonists on intracellular Ca(2+) concentration ([Ca(2+)](i)) and smooth muscle force were measured simultaneously using fura-PE3-loaded muscle preparations. Clonidine and UK14304 caused increases in [Ca(2+)](i) and force of the longitudinal muscle. The increases in [Ca(2+)](i) and muscle force were markedly inhibited by verapamil and in Ca(2+)-free solution (EGTA, 1 mM). In the absence of external Ca(2+), clonidine caused only a small increase in [Ca(2+)](i) in Ca(2+)-loaded preparations compared with those increases caused by carbachol, histamine, and oxytocin. Ca(2+) (2.5 mM) caused increases in [Ca(2+)](i) and force of the longitudinal muscles in a Ca(2+)-free high K(+) solution. Clonidine concentration dependently potentiated the Ca(2+)-induced contraction without significantly changing the increase in [Ca(2+)](i), and this potentiation was inhibited by yohimbine. These results suggested that clonidine increases the Ca(2+) sensitivity of the contractile elements through activation of alpha(2)-adrenoceptors. During the development of the contractile response to clonidine (1 microM, 0-5 min), tissue cyclic AMP levels did not change significantly. In vitro treatment with pertussis toxin (1 microg/ml for 2 h) significantly decreased the contraction induced by clonidine without affecting the responses to carbachol and high K(+). The present results indicate that in porcine myometrium, alpha(2)-adrenoceptor stimulation caused contraction of the longitudinal muscles by mechanisms largely dependent on the influx of extracellular Ca(2+), probably through voltage-dependent Ca(2+) channels (VDCCs), and that the potentiation of the Ca(2+) sensitivity of the contractile elements is another mechanism of the contractile responses. These actions involve a pertussis-toxin-sensitive G protein (probably G(i) type) in the signal transduction pathway.
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PMID:The mechanisms of alpha(2)-adrenoceptor agonist-induced contraction in longitudinal muscle of the porcine uterus. 1070 23

We studied the effects of histamine H(3) receptor ligands on the release of endogenous acetylcholine from the isolated, vascularly perfused rat stomach. The stomach was perfused via the celiac artery with modified Krebs-Ringer solution containing physostigmine. Released acetylcholine from the portal vein was electrochemically measured using high-performance liquid chromatography and an enzyme system. Vagus nerves were electrically stimulated twice for 2 min (0.5 or 2.5 Hz). Acetylcholine release evoked at 2.5 Hz was slightly inhibited by histamine and effectively potentiated by thioperamide, a histamine H(3) receptor antagonist. Acetylcholine release evoked at 0.5 Hz in the presence of atropine was not influenced by thioperamide, but effectively inhibited by histamine, R-alpha-methylhistamine or imetit, histamine H(3) receptor agonists. These inhibitory effects were abolished by thioperamide or pertussis toxin. These results suggest that histamine attenuates acetylcholine release from vagus nerves through histamine H(3) receptor-mediated and pertussis toxin-sensitive mechanisms in the rat stomach.
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PMID:Histamine H(3) receptor-mediated inhibition of endogenous acetylcholine release from the isolated, vascularly perfused rat stomach. 1074 68

We have previously shown that acetylcholine-induced contraction of oesophageal circular muscle depends on activation of phosphatidylcholine selective phospholipase C and D, which result in formation of diacylglycerol, and of phospholipase 2 which produces arachidonic acid. Diacylglycerol and arachidonic acid interact synergistically to activate protein kinase C. We have therefore investigated the relationship between cytosolic Ca(2+) and activation of phospholipase A(2) in response to acetylcholine-induced stimulation, by measuring the intracellular free Ca(2+) ([Ca(2+)]i), muscle tension, and [3H] arachidonic acid release. Acetylcholine-induced contraction was associated with increased [Ca(2+)]i and arachidonic acid release in a dose-dependent manner. In Ca(2+)-free medium, acetylcholine did not produce contraction, [Ca(2+)]i increase, and arachidonic acid release. In contrast, after depletion of Ca(2+) stores by thapsigargin (3 microM), acetylcholine caused a normal contraction, [Ca(2+)]i increase and arachidonic acid release. The increase in [Ca(2+)]i and arachidonic acid release were attenuated by the M2 receptor antagonist methoctramine, but not by the M3 receptor antagonist p-fluoro-hexahydro siladifenidol. Increase in [Ca(2+)]i and arachidonic acid release by acetylcholine were inhibited by pertussis toxin and C3 toxin. These findings indicate that contraction and arachidonic acid release are mediated through muscarinic M2 coupled to Gi or rho protein activation and Ca(2+) influx. Acetylcholine-induced contraction and the associated increase in [Ca(2+)]i and release of arachidonic acid were completely reduced by the combination treatment with a phospholipase A(2) inhibitor dimethyleicosadienoic acid and a phospholipase D inhibitor pCMB. They increased by the action of the inhibitor of diacylglycerol kinase R59949, whereas they decreased by a protein kinase C inhibitor chelerythrine. These data suggest that in oesophageal circular muscle acetylcholine-induced [Ca(2+)]i increase and arachidonic acid release are mediated through activation of M2 receptor coupled to Gi or rho protein, resulting in the activation of phospholipase A(2) and phospholipase D to activate protein kinase C.
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PMID:Increase of [Ca(2+)]i and release of arachidonic acid via activation of M2 receptor coupled to Gi and rho proteins in oesophageal muscle. 1078 28

It has been reported that acetylcholine hyperpolarizes the maximum diastolic potential of canine Purkinje fibers through a pathway involving a G protein and induces a decrease in their automaticity. It is unclear, however, whether the negative chronotropic action of acetylcholine in the presence of beta-adrenergic stimulation is due to the hyperpolarization of the maximum diastolic potential or a decrease in the slope of phase 4 depolarization. We used standard microelectrode techniques to study the negative chronotropic mechanism of acetylcholine in the presence of isoproterenol in adult canine Purkinje fibers. Fibers were incubated for 24 hours in Tyrode's solution alone (n = 10) or plus pertussis toxin (n = 10), and then superfused with acetylcholine (10(-9) to 10(-4) M) in the presence of isoproterenol (10(-7) M). Acetylcholine in the presence of isoproterenol significantly decreased automaticity without hyperpolarization of the maximum diastolic potential, and decreased the slope of phase 4 depolarization. The effects of acetylcholine on automaticity and the slope of phase 4 depolarization were attenuated by pertussis toxin. The present findings indicate that the negative chronotropic action of acetylcholine in the presence of isoproterenol is due to the decrease in the slope of phase 4 depolarization through a pathway involving a pertussis toxin-sensitive G protein and that it is not the result of hyperpolarization of the maximum diastolic potential.
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PMID:Hyperpolarization is not responsible for the acetylcholine-induced negative chronotropic action in the presence of isoproterenol. 1119 64

I suggested in the accompanying article [Mol Pharmacol 2001;59:875-885] that muscarinic receptors catalyzed G protein activation. Acetylcholine or carbamylcholine recognition facilitated not only the GDP release from receptor-coupled inactive G proteins but also the release of G from the (unstable) HRG complex. The two effects facilitated [(35)S]GTP gamma S binding in the presence of GDP, but could be studied separately by comparing [(35)S]GTP gamma S binding in the absence and presence of GTP. Guanyl nucleotides affected the efficiency of receptor-G protein coupling. The relative efficacies of partial agonists in the absence and presence of GTP should remain nonlinearly correlated if all agonists stabilize (to different extents) the same active receptor conformation. The correlation between M(1) muscarinic agonists' efficacy in accelerating [(35)S]GTP gamma S binding in the absence of other nucleotides and their in vivo efficacy (inositol phosphate accumulation) was in fact very poor. This probably reflected the presence of GTP in intact cells: pertussis toxin pretreatment (which inactivates the G(i/o) proteins) did not affect the agonists' efficacy profile (evaluated in the absence of spare receptors), but the addition of GTP to the [(35)S]GTP gamma S binding medium did. These results did not support the allosteric "two states" model of receptor activation, but suggested that different agonists induced different receptor conformations ("induced fit").
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PMID:Activation of guanosine 5'-[gamma-(35)S]thio-triphosphate binding through M(1) muscarinic receptors in transfected Chinese Hamster ovary cell membranes: 2. Testing the "two-states" model of receptor activation. 1125 34

Acetylcholine (ACh) activates two types of chloride conductances in Aplysia neurons that can be distinguished by their kinetics and pharmacology. One is a rapidly desensitizing current that is blocked by alpha-conotoxin-ImI and the other is a sustained current that is insensitive to the toxin. These currents are differentially expressed in Aplysia neurons. We report here that neurons that respond to ACh with a sustained chloride conductance also generate 8-lipoxygenase metabolites. The sustained chloride conductance and the activation of 8-lipoxygenase have similar pharmacological profiles. Both are stimulated by suberyldicholine and nicotine, and both are inhibited by alpha-bungarotoxin. Like the sustained chloride conductance, the activation of 8-lipoxygenase is not blocked by alpha-conotoxin-ImI. In spite of the similarities between the metabolic and electrophysiological responses, the generation of 8-lipoxygenase metabolites does not appear to depend on the ion current since an influx of chloride ions is neither necessary nor sufficient for the formation of the lipid metabolites. In addition, the application of pertussis toxin blocked the ACh-activated release of arachidonic acid and the subsequent production of 8-lipoxygenase metabolites, yet the ACh-induced activation of the chloride conductance is not dependent on a G protein. Our results are consistent with the idea that the nicotinic ACh receptor that activates the sustained chloride conductance can, independent of the chloride ion influx, initiate lipid messenger synthesis.
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PMID:A pertussis toxin-sensitive 8-lipoxygenase pathway is activated by a nicotinic acetylcholine receptor in aplysia neurons. 1135 29

We have studied the role of M(2) and M(3) muscarinic receptors in acetylcholine-mediated desensitization of the contractile response to histamine in the guinea pig ileum. Treatment of the isolated ileum with acetylcholine (30 microM) for 20 min caused a marked desensitization of the contractile response to histamine. When measured 5 min after washout of acetylcholine, the EC(50) value of histamine increased 5.8-fold compared with that estimated before acetylcholine treatment, whereas the maximal response was unaffected. This shift in the EC(50) value of histamine was maximal at the earliest time measured after acetylcholine treatment (5 min), and normal sensitivity recovered in approximately 20 min. Acetylcholine-induced desensitization was prevented by uncoupling of M(2) receptors from G(i) with pertussis toxin or by selective inactivation of M(3) receptors with N-2-chloroethyl-4-piperidinyl diphenylacetate (4-DAMP mustard). The shifts in the EC(50) values of histamine measured 5 min after acetylcholine treatment were only 2.0- and 1.8-fold in pertussis toxin- and 4-DAMP mustard-treated ilea, respectively. Both pertussis toxin- and 4-DAMP mustard-treatment had little or no effect on histamine-induced contractions in control ileum. Measurement of histamine-stimulated inositol phosphate accumulation in the longitudinal muscle of the ileum showed little or no inhibitory effect of prior exposure to acetylcholine, indicating that the majority of the heterologous desensitization occurs downstream from phospholipase Cbeta activation. Collectively, our results suggest that activation of both M(2) and M(3) receptors is required for heterologous desensitization of histamine-mediated contractions in the guinea pig ileum.
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PMID:Acetylcholine-induced desensitization of the contractile response to histamine in Guinea pig ileum is prevented by either pertussis toxin treatment or by selective inactivation of muscarinic M(3) receptors. 1135 41

Nefiracetam is a new pyrrolidone nootropic drug that is being developed for clinical use in the treatment of post-stroke vascular-type and Alzheimer's-type dementia. Among a few neuroreceptors that have been identified as potential targets of nootropics, neuronal nicotinic acetylcholine receptors (nnAChRs) are deemed the most important since they are related to learning, memory, and Alzheimer's disease dementia. We have recently found potent stimulating action of nefiracetam on nnAChRs. Rat cortical neurons in long-term primary culture expressed nnAChRs. Whole-cell patch clamp experiments revealed two types of currents induced by ACh, alpha-bungarotoxin (alpha-BuTX)-sensitive, rapidly desensitizing, alpha 7-type currents and alpha-BuTX-insensitive, slowly desensitizing, alpha 4 beta 2-type currents. Although alpha 7-type currents were only weakly inhibited by nefiracetam, alpha 4 beta 2-type currents were potently and efficaciously potentiated by nefiracetam. Nefiracetam at 0.1 nM reversibly potentiated ACh-induced currents to 200-300% of control. Very high concentrations (about 10 microM) also potentiated these currents, but to a lesser extent, indicative of the bell-shaped dose-response relationship known to occur for nefiracetam, even in animal behavior experiments. Three specific inhibitors of each of PKA and PKC did not prevent nefiracetam from potentiating ACh-induced currents, indicating that these protein kinases are not involved in nefiracetam action. Pretreatment with pertussis toxin did not alter nefiracetam potentiation, indicating Gi/Go proteins are not involved. Pretreatment with cholera toxin did abolish nefiracetam potentiation. Thus, nefiracetam potentiation is mediated via Gs proteins. In conclusion, nefiracetam stimulates alpha 4 beta 2-type nnAChRs via Gs proteins at nanomolar concentrations. The potentiation of alpha 4 beta 2-type nnAChRs is thought to be at least partially responsible for cognitive enhancing action.
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PMID:Post-stroke dementia. Nootropic drug modulation of neuronal nicotinic acetylcholine receptors. 1146 69

1. The effects that muscarinic receptor stimulation have on the cAMP-dependent regulation of L-type Ca(2+) currents were studied in isolated guinea-pig ventricular myocytes using the whole-cell configuration of the patch-clamp technique. 2. The muscarinic agonist ACh inhibited the Ca(2+) current stimulated by the beta-adrenergic agonist isoprenaline (Iso), and washout of ACh revealed a stimulatory response that appeared as a transient rebound increase in the amplitude of the Ca(2+) current. The ACh-induced stimulatory effect was not observed in the absence of Iso. 3. ACh-induced rebound stimulation was also observed in the presence of H(2) histamine receptor activation and cholera toxin treatment, which like beta-adrenergic receptor activation enhance adenylyl cyclase (AC) activity in a stimulatory G protein (G(s))-dependent manner. ACh-induced rebound stimulation was not observed in the presence of forskolin, which enhances AC activity in a G(s)-independent manner. 4. Pertussis toxin (PTX) treatment blocked both the stimulatory and inhibitory effects of ACh. Intracellular dialysis with QEHA, a peptide that binds free G protein betagamma subunits, selectively antagonized the stimulatory effect, leaving an enhanced inhibitory effect. 5. Evidence for the expression of AC4, an isoform of AC that can be stimulated by Gbetagamma but only in the presence of Galpha(s), was obtained by Western blot analysis of guinea-pig ventricular myocyte membrane preparations. 6. These results suggest that muscarinic receptor stimulation facilitates as well as inhibits cAMP-dependent regulation of the Ca(2+) current and that the net response is a balance between these two actions. We suggest that the stimulatory effect is due to a direct activation of AC4 by the betagamma subunits of a PTX-sensitive G protein.
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PMID:ACh-induced rebound stimulation of L-type Ca(2+) current in guinea-pig ventricular myocytes, mediated by Gbetagamma-dependent activation of adenylyl cyclase. 1169 64

We have shown that ginsenoside Rf (Rf) regulates voltage-dependent Ca(2+) channels through pertussis toxin (PTX)-sensitive G proteins in rat sensory neurons. These results suggest that Rf can act through a novel G protein-linked receptor in the nervous system. In the present study, we further examined the effect of Rf on G protein-coupled inwardly rectifying K(+) (GIRK) channels after coexpression with size-fractionated rat brain mRNA and GIRK1 and GIRK4 (GIRK1/4) channel cRNAs in Xenopus laevis oocytes using two-electrode voltage-clamp techniques. We found that Rf activated GIRK channel in a dose-dependent and reversible manner after coexpression with subfractions of rat brain mRNA and GIRK1/4 channel cRNAs. This Rf-evoked current was blocked by Ba(2+), a potassium channel blocker. The size of rat brain mRNA responding to Rf was about 6 to 7 kilobases. However, Rf did not evoke GIRK current after injection with this subfraction of rat brain mRNA or GIRK1/4 channel cRNAs alone. Other ginsenosides, such as Rb(1) and Rg(1), evoked only slight induction of GIRK currents after coexpression with the subfraction of rat brain mRNA and GIRK1/4 channel cRNAs. Acetylcholine and serotonin almost did not induce GIRK currents after coexpression with the subfraction of rat brain mRNA and GIRK1/4 channel cRNAs. Rf-evoked GIRK currents were not altered by PTX pretreatment but were suppressed by intracellularly injected guanosine-5'-(2-O-thio) diphosphate, a nonhydrolyzable GDP analog. These results indicate that Rf activates GIRK channel through an unidentified G protein-coupled receptor in rat brain and that this receptor can be cloned by the expression method demonstrated here.
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PMID:Functional expression of a novel ginsenoside Rf binding protein from rat brain mRNA in Xenopus laevis oocytes. 1190 Dec 33

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