Funcdonal characterization of the muscarinic receptor in rat lungs

Post, Mark J.; Biesebeek, J.D. te; Doods, Henri; Wemer, J.; Rooij, H.H. van; Porsius, A. J.

doi:10.1016/0014-2999(91)90254-n

Cited by 17 publications

(6 citation statements)

References 19 publications

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“…A comparison of the IC 50 values of each antagonist shows that 4‐DAMP, a selective M 3 antagonist, was much more potent than the M 1 antagonist, pirenzepine and the M 2 antagonist, methoc‐tramine. The pA 2 values calculated, in contraction experiments, for each of the antagonists are in good agreement with previously published data in rat and mouse trachea (Post et al , 1991; Garssen et al , 1993). Furthermore, since the Schild regressions were linear and since the slope was not different from unity for each of the antagonists, the pA 2 value can be considered as an estimate of the p K B (Kenakin, 1993) and thus can be compared to its value determined in binding studies for the different muscarinic receptor subtypes, M 1 , M 2 and M 3 (Eglen et al , 1994).…”

Section: Discussionsupporting

confidence: 90%

“…Various subtypes of muscarinic receptor have been identified in the lung (Barnes, 1993; Haddad et al , 1994) and M 2 and M 3 receptor subtypes have been found in rat airway smooth muscle (Gies et al , 1989), although there are large interspecies variations in subtype expression. Functional studies have shown a major role of the M 3 receptor subtype in broncho‐constriction (Post et al , 1991; Garsen et al , 1993) and, although radioligand binding studies have indicated a high proportion of M 2 receptors in airway smooth muscle (Fryer & El‐Fakahany, 1990; Haddad et al , 1994), the role of this subtype remains rather unclear (Fernandes et al , 1992; Eglen et al , 1994; Roffel et al , 1995). We assessed the action of four muscarinic cholinoceptor antagonists over a wide range of concentrations on the [Ca 2+ ] i response to ACh.…”

Section: Discussionmentioning

confidence: 99%

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[Ca²⁺]_i oscillations induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity

Roux

Guibert

Savineau

et al. 1997

British J Pharmacology

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1 Cytosolic calcium concentration ([Ca 2+ ] i ) by indo 1 microspectro¯uorimetry in freshly isolated cells and isometric contraction of isolated rings were measured in response to muscarinic cholinoceptor stimulation in rat tracheal smooth muscle. 2 In isolated myocytes, acetylcholine (ACh, 0.03 ± 1 mM) caused a rapid and graded increase in [Ca 2+ ] i up to a net amplitude of 492+26 nM (n=19) which gradually declined. The EC 50 for ACh was 0.13 mM. This ®rst [Ca ] i response to ACh but with a higher IC 50 of 2 mM. Methoctramine (a selective M 2 antagonist) up to a concentration of 10 mM caused only a 40% inhibition. The eect of muscarinic antagonists on cumulative concentration-response curves (CCRC) for carbachol was assessed at the following concentrations: atropine and 4-DAMP at 3, 10 and 30 nM; pirenzepine 0.3, 1 and 3 mM, and methoctramine at 1, 3 and 10 mM. For these concentrations, all of the antagonists produced a rightward shift of the CCRC for carbachol and pA 2 values were 9. 2, 8.8, 6.7 and 6.3, respectively. 5 In conclusion, the present study indicates that muscarinic stimulation of rat isolated tracheal smooth muscle cells induces [Ca 2+ ] i oscillations. The occurrence of these oscillations depends on the graded amplitude of the ®rst [Ca 2+ ] i rise and their frequency may play a role in the amplitude of the mechanical activity in response to muscarinic cholinoceptor activation. Both the [Ca 2+ ] i and the contractile responses are primarily dependent on activation of the M 3 receptor subtype.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

[Ca²⁺]_i oscillations induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity

Roux

Guibert

Savineau

et al. 1997

British J Pharmacology

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“…Up to 91% of muscarinic receptor protein in rat lung is of the M 2 subtype with M 3 receptor protein making up most of the remainder 8. The apparently small number of M 3 receptors has, however, been reported to dominate muscarinic responses 7. It is therefore possible that a small number of M 1 receptors will still be sufficient to produce a physiological response.…”

Section: Discussionmentioning

confidence: 99%

“…6 A species difference in distribution of muscarinic receptors of the lung has been established. In isolated rat lung, stimulation of the M 3 receptor subtype is responsible for acetylcholine induced bronchoconstriction 7. However, previous experiments in our laboratory using alveolar capsules in puppies have shown that the peripheral lung responses to inhaled methacholine were antagonised by the M 1 selective blocker pirenzepine 8…”

mentioning

confidence: 99%

Muscarinic blockade of methacholine induced airway and parenchymal lung responses in anaesthetised rats

Tulic

Wale²,

Peták³

et al. 1999

Thorax

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Background-It has previously been shown that M 1 cholinergic receptors are involved in the parenchymal response to inhaled methacholine in puppies using the M 1 selective antagonist pirenzepine. Although M 3 receptors are responsible for acetylcholine induced bronchoconstriction in isolated rat lung, the role of M 1 receptors has not been determined in the rat in vivo. Methods-Anaesthetised, paralysed, open chested Brown Norway rats were mechanically ventilated and the femoral vein cannulated for intravenous injection of drugs. Low frequency forced oscillations were applied to measure lung input impedance (ZL) and computerised modelling enabled separation of ZL into airway and parenchymal components. Atropine (500 µg/kg iv) and pirenzepine (50, 100 or 200 µg/kg iv) were administered during steady state constriction generated by continuous inhalation (1 mg/ml) or intravenous (10 or 15 µg/kg/min) administration of methacholine. Results-Continuous inhalation of methacholine produced a 185% increase in frequency dependent tissue resistance (G) which was eVectively inhibited by atropine 500 µg/kg iv (p<0.01, n = 6). Pirenzepine (50, 100 or 200 µg/kg) had a minimal eVect on the parenchymal response to inhaled methacholine. A 258% increase in airway resistance (Raw) was induced by continuous intravenous infusion of methacholine and this response was eVectively abolished by pirenzepine (p<0.001, n = 5). Cutting the vagi in the cervical region did not alter baseline airway mechanics. Vagotomy did not aVect lung responses to intravenous methacholine nor the ability of pirenzepine to reduce these responses. Conclusions-In the rat, M 1 -subtype receptors are functional in airways but not in the tissue. (Thorax 1999;54:531-537) Keywords: forced oscillation technique; muscarinic blockade; lung parenchyma Methacholine is commonly used as a challenge agent for the assessment of hyperresponsiveness in asthmatic subjects. It is a chemical analogue of acetylcholine and induces smooth muscle contraction by stimulating muscarinic cholinergic receptors located on the smooth muscle. In a number of animal studies the way in which methacholine alters lung function has been shown to depend on the route of delivery. Intravenous methacholine acts mainly on the airway producing an increase in airway resistance whereas inhaled methacholine alters the mechanical properties of both the airways and the lung tissues.1-3 One possible explanation for these findings is that diVerent receptors are involved.Muscarinic cholinergic receptors exist in at least four major subtypes that can be demonstrated pharmacologically. 4 Multiple subtypes have, however, been identified biochemically in the lung and binding studies have shown the presence of M 1 , M 2 and M 3 subtypes.5 6 A species diVerence in distribution of muscarinic receptors of the lung has been established. In isolated rat lung, stimulation of the M 3 receptor subtype is responsible for acetylcholine induced bronchoconstriction.7 However, previous experiments in our laboratory using...

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“…Although it is quite likely that the enterochromaffinlike cells, recently isolated from the canine gastric muco sa, are the source of the secretagogue-stimulated hista mine release [3], the canine gastric mucosa is very rich in mast cells, and it has not been determined with certainty that the mast cell histamine content has no effect on gas tric mucosal histamine release [19], Adenosine via A| receptors has been shown to enhance stimulated hista mine release from canine gastric mast cells as well as from human and rodent pulmonary mast cells [2,[20][21][22], The effect of adenosine can be inhibited with the adenosine receptor antagonist theophylline, and the possibility that theophylline ameliorates asthma by inhibiting mediator release has been proposed by several investigators [23], Our data demonstrated that adenosine infused to gas tric arterial concentrations of 30 and 100 \xM had no sig nificant effect on pentagastrin-stimulated gastric hista mine release. Although the between-dog variability in response to pentagastrin was large, overall the effect of the two concentrations of adenosine was not statistically dif ferent from the vehicle.…”

Section: Discussionmentioning

confidence: 99%

Effect of Adenosine and Histamine Receptor Stimulation on Canine Histamine Release to Pentagastrin

Payne

Gerber²

1997

Digestion

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The effects of adenosine and histamine 2 and histamine 3 receptor agonists on the regulation of gastric histamine release were examined in anesthetized mixed-breed dogs. All compounds were infused directly into the gastrosplenic artery to avoid perturbations in systemic hemodynamics, and the gastric histamine release was stimulated with pentagastrin. The histamine concentration in plasma samples was measured utilizing gas chromatography-negative-ion chemical ionization mass spectroscopy. Pentagastrin consistently stimulated gastric histamine release with the peak stimulation occurring at 5 min, while neither 30 nor 100 μM of adenosine altered the effect of pentagastrin on histamine release. In addition, theophylline at 20 μg/ml exhibited no effect on stimulated histamine release. The histamine 2 receptor agonist dimaprit, at 1 and 3 μM, attenuated pentagastrin-stimulated histamine release at the 5-min time period, but the difference was not sustained at later time points (histamine release from 1.4 ± 0.6 to 92 ± 18 ng/min at 5 min with pentagastrin alone; from 1.2 ± 0.5 to 32 ± 11 ng/min with pentagastrin plus 1 μM dimaprit, and from 2.0 ± 1.1 to 32 ± 9 ng/min with pentagastrin plus 3 μM dimaprit), while the H₂ receptor antagonist cimetidine exhibited no effect on pentagastrin-stimulated histamine release. The histamine 3 receptor agonist (R)-α-methyl-histamine attenuated the pentagastrin-stimulated histamine release at the 5-and 10-min time periods only at 1 μM without showing any effect at the higher (3 μM) concentration. Thioperamide, a H₃ receptor antagonist, did not modify pentagastrin-stimulated histamine release. These data demonstrate that adenosine has no modulatory role on gastric histamine release, but histamine via H₂ and H₃ histamine receptors could modulate its own release but only to a modest degree as compared with the potent effect of the paracrine hormone somatostatin.

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Funcdonal characterization of the muscarinic receptor in rat lungs

Cited by 17 publications

References 19 publications

[Ca²⁺]_i oscillations induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity

[Ca²⁺]_i oscillations induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity

Muscarinic blockade of methacholine induced airway and parenchymal lung responses in anaesthetised rats

Effect of Adenosine and Histamine Receptor Stimulation on Canine Histamine Release to Pentagastrin

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Funcdonal characterization of the muscarinic receptor in rat lungs

Cited by 17 publications

References 19 publications

[Ca2+]i oscillations induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity

[Ca2+]i oscillations induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity

Muscarinic blockade of methacholine induced airway and parenchymal lung responses in anaesthetised rats

Effect of Adenosine and Histamine Receptor Stimulation on Canine Histamine Release to Pentagastrin

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[Ca²⁺]_i oscillations induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity

[Ca²⁺]_i oscillations induced by muscarinic stimulation in airway smooth muscle cells: receptor subtypes and correlation with the mechanical activity