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H Meurs

Publications and source records attributed to H Meurs.

At least 37 records · Page 2Linked to original sources
PubMed1996

Modulation of agonist-induced phosphoinositide metabolism, Ca2+ signalling and contraction of airway smooth muscle by cyclic AMP-dependent mechanisms.

1. The effects of increased cellular cyclic AMP levels induced by isoprenaline, forskolin and 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cyclic AMP) on phosphoinositide metabolism and changes in intracellular Ca2+ elicited by methacholine and histamine were examined in bovine isolated tracheal smooth muscle (BTSM) cells. 2. Isoprenaline (pD2 (-log10 EC50) = 6.32 +/- 0.24) and forskolin (pD2 = 5.6 +/- 0.05) enhanced cyclic AMP levels in a concentration-dependent fashion in these cells, while methacholine (pD2 = 5.64 +/- 0.12) and histamine (pD2 = 4.90 +/- 0.04) caused a concentration-related increase in [3H]-inositol phosphates (IP) accumulation in the presence of 10 mM LiCl. 3. Preincubation of the cells (5 min, 37 degrees C) with isoprenaline (1 microM), forskolin (10 microM) and 8-Br-cyclic AMP (1 mM) did not affect the IP accumulation induced by methacholine, but significantly reduced the maximal IP production by histamine (1 mM). However, the effect of isoprenaline was small (15.0 +/- 0.6% inhibition) and insignificant at histamine concentrations between 0.1 and 100 microM. 4. Both methacholine and histamine induced a fast (max. in 0.5-2 s) and transient increase of intracellular Ca2+ concentration ([Ca2+]i) followed by a sustained phase lasting several minutes. EGTA (5 mM) attenuated the sustained phase, indicating that this phase depends on extracellular Ca2+. 5. Preincubation of the cells (5 min, 37 degrees C) with isoprenaline (1 microM), forskolin (10 microM) and 8-Br-cyclic AMP (1 microM) significantly attenuated both the Ca(2+)-transient and the sustained phase generated at equipotent IP producing concentrations of 1 microM methacholine and 100 microM histamine (approx. 40% of maximal methacholine-induced IP response), but did not affect changes in [Ca2+]i induced by 100 microM methacholine (95.2 +/- 3.5% of maximal methacholine-induced IP response). 6. Significant correlations were found between the isoprenaline-induced inhibition of BTSM contraction and inhibition of Ca2+ mobilization or influx induced by methacholine and histamine, that were similar for each contractile agonist. 7. These data indicate that (a) cyclic AMP-dependent inhibition of Ca2+ mobilization in BTSM cells is not primarily caused by attenuation of IP production, suggesting that cyclic AMP induced protein kinase A (PKA) activation is effective at a different level in the [Ca2+]i homeostasis, (b) that attenuation of intracellular Ca2+ concentration plays a major role in beta-adrenoceptor-mediated relaxation of methacholine- and histamine-induced airway smooth muscle contraction, and (c) that the relative resistance of the muscarinic agonist-induced contraction to beta-adrenoceptor agonists, especially at (supra) maximal contractile concentrations is largely determined by its higher potency in inducing intracellular Ca2+ changes.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Deficiency of nitric oxide in allergen-induced airway hyperreactivity to contractile agonists after the early asthmatic reaction: an ex vivo study.

1. Using a guinea-pig model of allergic asthma, we investigated the role of nitric oxide (NO) in allergen-induced airway hyperreactivity after the early asthmatic reaction, by examining the effects of the NO-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) on the responsiveness to methacholine and histamine of isolated perfused tracheae from unchallenged (control) animals and from animals 6 h after ovalbumin challenge. 2. All animals developed airway hyperreactivity to inhaled histamine at 6 h after ovalbumin challenge, with a mean 3.11 +/- 0.45 fold increase in sensitivity to the agonist (P < 0.001). 3. In perfused tracheal preparations from the ovalbumin-challenged guinea-pigs, the maximal responses (Emax) to methacholine and histamine were significantly enhanced compared to controls, both after intraluminal (IL) and extraluminal (EL) administration of the contractile agonists. In addition, a small but significant increase in the pD2 (-log10 EC50) for IL and EL methacholine and for IL histamine was observed. As a consequence, the delta pD2 (EL-IL) for histamine was slightly decreased from 1.67 +/- 0.13 to 1.23 +/- 0.14 (P < 0.05). However, the delta pD2 for methacholine was unchanged (1.85 +/- 0.11 and 1.77 +/- 0.12, respectively; NS). 4. Incubation of control tracheae with 100 microM L-NAME (IL) significantly enhanced the Emax for both IL and EL methacholine and histamine to approximately the same degree as observed after ovalbumin challenge, with no effect on the pD2 and delta pD2 for both agonists. On the contrary, L-NAME had no effect on Emax and pD2 values of tracheal preparations from ovalbumin-challenged guinea-pigs. 5. L-NAME (10 microM-1 mM) had no effect on methacholine-induced contraction of isolated tracheal strip preparations obtained from control animals, indicating that L-NAME has no antimuscarinic effect on tracheal smooth muscle. 6. Histological examination of the intact tracheal preparations indicated epithelial and subepithelial infiltration of eosinophils after ovalbumin challenge. However, no apparent damage of the airway epithelium was observed in these preparations. 7. The results indicate that a deficiency of NO contributes to allergen-induced airway hyperreactivity after the early asthmatic reaction and that this deficiency appears not to be due to epithelial shedding.

Allergens↗
PubMed1995

Phosphodiesterase inhibitors reduce bronchial hyperreactivity and airway inflammation in unrestrained guinea pigs.

A new guinea pig model of allergic asthma was used to investigate the effects of low doses of the phosphodiesterase inhibitors, rolipram (phosphodiesterase IV selective), ORG 20241 (N-hydroxy-4-(3,4-dimethoxyphenyl)-thiazole-2-carboximidamide; dual phosphodiesterase III/IV inhibitor with some selectivity for the phosphodiesterase IV isoenzyme), and of theophylline (non-selective) on allergen-induced early and late phase asthmatic reactions, bronchial hyperreactivity to histamine inhalation, and airway inflammation. Theophylline (25 mg/kg i.p.) and ORG 20241 (5 mg/kg i.p.) did not affect histamine-induced bronchoconstriction, whereas rolipram (75 micrograms/kg i.p.) only slightly reduced the response to histamine at 7 h after administration. However, bronchial hyperreactivity after the early and after the late reaction was significantly reduced by theophylline, rolipram and ORG 20241, while bronchoalveolar lavage studies revealed a selective inhibition of airway inflammation by the phosphodiesterase inhibitors. Theophylline significantly reduced the number of eosinophils, neutrophils and macrophages; rolipram reduced the number of neutrophils and lymphocytes, and ORG 20241, the number of eosinophils and macrophages. None of the compounds at the dosage indicated reduced the early and late reaction when administered i.p. 1 h before allergen exposure to defined dual responding animals. These results indicate that non-bronchodilator doses of these phosphodiesterase inhibitors markedly reduce the allergen-induced development of bronchial hyperreactivity as well as airway inflammation, presumably by selectively inhibiting cellular migration. The results suggest that an orchestrated series of cellular interactions is involved in the development of bronchial hyperreactivity. It is concluded that phosphodiesterase inhibitors may be very useful in the treatment of bronchial asthma.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Contribution of a cholinergic reflex mechanism to allergen-induced bronchial hyperreactivity in permanently instrumented, unrestrained guinea-pigs.

1. In conscious, permanently instrumented, unrestrained, ovalbumin-sensitized guinea-pigs the development of allergen-induced bronchial hyperreactivity to histamine- and methacholine-inhalation was investigated after the early as well as after the late asthmatic response. 2. The allergen-induced increase in bronchial reactivity to histamine was significantly higher than to methacholine. 3. The muscarinic receptor antagonist, ipratropium bromide (1.0 mM, 3 min inhalation), blocked methacholine-induced bronchoconstriction and caused a significant 1.7 fold inhibition of the histamine-induced bronchoconstriction of control animals. 4. A lower dose of ipratropium bromide (0.1 mM, 3 min inhalation) had no significant effect on histamine-induced bronchoconstriction in control animals, but significantly reduced the allergen-induced increase in bronchial reactivity to histamine between the early and late asthmatic response. At 1.0 mM ipratropium bromide, no further reduction was observed. 5. These results clearly indicate that an exaggerated cholinergic reflex mechanism contributes to allergen-induced bronchial hyperreactivity to histamine.

Allergens↗
PubMed1995

No evidence for a role of muscarinic M2 receptors in functional antagonism in bovine trachea.

1. The functional antagonism between methacholine- or histamine-induced contraction and beta-adrenoceptor-mediated relaxation was evaluated in bovine tracheal smooth muscle in vitro. In addition, the putative contribution of muscarinic M2 receptors mediating inhibition of beta-adrenoceptor-induced biochemical responses to this functional antagonism was investigated with the selective muscarinic antagonists, pirenzepine (M1 over M2), AF-DX 116 and gallamine (M2 over M3), and hexahydrosiladiphenidol (M3 over M2). 2. By use of isotonic tension measurement, contractions were induced with various concentrations of methacholine or histamine, and isoprenaline concentration-relaxation curves were obtained in the absence or presence of the muscarinic antagonists. Antagonist concentrations were chosen so as to produce selective blockade of M2 receptors (AF-DX 116 0.1 microM, gallamine 30 microM), or half-maximal blockade of M3 receptors (pirenzepine 0.1 microM, AF-DX 116 0.5 microM, hexahydrosiladiphenidol 0.03 microM). Since these latter antagonist concentrations mimicked KB values towards bovine tracheal smooth muscle M3 receptors, antagonist-induced decreases in contractile tone were compensated for by doubling the agonist concentration. 3. It was found that isoprenaline-induced relaxation of bovine tracheal smooth muscle preparations was dependent on the nature and the concentration of the contractile agonist used. Thus, isoprenaline pD2 (-log EC50) values were decreased 3.7 log units as a result of increasing cholinergic tone from 22 to 106%, and 2.4 log units by increasing histamine tone over a similar range. Furthermore, maximal relaxability of cholinergic tone decreased gradually from 100% at low to only 1.3% at supramaximal contraction levels, whereas with histamine almost complete relaxation was maintained at all concentrations applied. As a result, isoprenaline relaxation was clearly hampered with methacholine compared to histamine at equal levels of contractile tone.4. In the presence of gallamine, isoprenaline relaxation was facilitated for most concentrations of methacholine, and for all concentrations of histamine. These changes could be explained by the decreased contraction levels for both contractile agonists in the presence of gallamine.5. Isoprenaline-induced relaxation of cholinergic contraction was also facilitated by AF-DX 116 as well as by pirenzepine and hexahydrosiladiphenidol, and these (small) changes were again related to the(small) decreases in cholinergic contraction levels that were present in these experiments despite the additional administration of the agonist to readjust contractile tone. Similarly, changes in isoprenaline relaxation of histamine-induced tone could be explained by different contraction levels.6. These results can be explained by the sole involvement of muscarinic M3 receptors, and provide no evidence for a role of muscarinic M2 receptors in functional antagonism in bovine trachea. Furthermore,they stress the importance of taking into account non-cholinergic controls as well as contraction levels in these experiments.

Animals↗
PubMed1994

Dissociation between bronchial hyperreactivity in vivo and reduced beta-adrenoceptor sensitivity in vitro in allergen-challenged guinea pigs.

In a recently developed guinea pig model of allergic asthma, we investigated the relationships between allergen-induced bronchial hyperreactivity in vivo, tracheal smooth muscle function in vitro, and the number of inflammatory cells in the bronchoalveolar lavage. At 6 h after allergen provocation (after the early asthmatic reaction) bronchial hyperreactivity to histamine aerosol was observed, which was still present, but reduced, at 24 h after the challenge (after the late asthmatic reaction). The severity of bronchial hyperreactivity at 6 h and at 24 h after each of four daily allergen provocations was progressively reduced. The contractile properties of tracheal smooth muscle preparations in response to methacholine or histamine were not changed at 6 h and 24 h after a single allergen provocation, as well as at 24 h after the fourth of the repeated provocations. However, the sensitivity to isoprenaline-induced relaxation of a half-maximal contraction obtained with methacholine or histamine was significantly reduced at 24 h after either a single or the fourth of the repeated provocations. The time course of the reduced beta-adrenoceptor sensitivity in vitro did not correlate with that of bronchial hyperreactivity in vivo. However, it was parallelled by a progressive infiltration of inflammatory cells in the airways, suggesting that mediators from these cells may decrease airway smooth muscle beta-adrenoceptor sensitivity.

Allergens↗
PubMed1994

Role of histamine in allergen-induced asthmatic reactions, bronchial hyperreactivity and inflammation in unrestrained guinea pigs.

In a new model using conscious, unrestrained and ovalbumin-sensitized guinea pigs, we investigated the effects of the selective histamine H1 receptor antagonist, mepyramine, on the development of allergen-induced early and late asthmatic reactions, bronchial hyperreactivity and airway inflammation, having each animal as its own control. In guinea pigs responding to a first allergen exposure with an early as well as a late asthmatic reaction (82% of the animals) a second, identical, allergen provocation was performed, in the absence (control) or presence of 1 mg/ml mepyramine aerosol, inhaled for 10 min, 1 h before provocation. The mepyramine treatment significantly reduced both early and late asthmatic reactions and prevented the development of bronchial hyperreactivity to histamine and methacholine after both reactions. Examination of the bronchoalveolar lavage fluid 24 h after the second allergen provocation revealed a general reduction of inflammatory cells after mepyramine treatment. The results indicate that histamine, released during the early asthmatic reaction, contributes to the development of the late asthmatic reaction as well as of early and late bronchial hyperreactivity, possibly via an effect on airway inflammation.

Allergens↗
PubMed1994

Relationships among allergen-induced early and late phase airway obstructions, bronchial hyperreactivity, and inflammation in conscious, unrestrained guinea pigs.

The relationship among allergen-induced early asthmatic reactions (EARs) and late asthmatic reactions (LARs), early (between EAR and LAR) and late (after LAR) changes in bronchial reactivity to histamine and infiltration of inflammatory cells into the airways were investigated with a new model of chronically instrumented, unrestrained, and ovalbumin-sensitized guinea pigs. Two different provocation strategies were examined. With the use of stepwise increasing allergen concentrations, all 21 animals responded with an EAR, which in 15 animals (71%) was followed by an LAR. By inhalation of a single allergen concentration for up to 15 minutes, 11 of 14 animals showed an EAR, which in 10 animals (71%) was followed by an LAR. One animal did not respond, whereas the remaining two showed only an LAR. At 6 hours (after the EAR) and 24 hours (after the LAR) after allergen provocation, a significant bronchial hyperreactivity (BHR) toward histamine aerosol was observed in the dual responding animals (both protocols), but not significant changes were observed in animals with a single EAR or a single LAR. Significant correlations were found between the initial increase in airway obstruction after allergen provocation and the severity of the EAR and LAR, as well as the early and late BHR; in addition, a significant correlation was found between the early and late BHR. In contrast, the severity of the LAR did not correlate with the BHR at 6 hours and 24 hours. At 6 hours, there was a marked tendency to an increase in the number of eosinophils and a significant increase in the number of neutrophils in the bronchoalveolar lavage. At 24 hours after provocation, the number of eosinophils and neutrophils was significantly enhanced. These data suggest that early activation of mast cells and/or inflammatory leukocytes may determine the development of the LAR, as well as the early and late BHR, although there appears to be no causal relationship between the BHR at both time points and the severity of the LAR. The relationships among allergen-induced EAR and LAR, early and late BHR, and airway inflammation observed in this new guinea pig model are strikingly similar to those observed in patients with asthma.

Airway Obstruction↗
PubMed1994

The importance of eosinophil activation for the development of allergen-induced bronchial hyperreactivity in conscious, unrestrained guinea-pigs.

Using a newly developed guinea-pig model of asthma, characterized by allergen-induced early and late phase asthmatic reactions, bronchial hyperreactivity (BHR) and airway inflammation, the importance of eosinophil activation for the development of BHR to inhaled histamine was investigated at 6 h (after the early reaction) and 24 h (after the late reaction) after allergen provocation. Eosinophil activation was assessed by a sensitive kinetic assay for eosinophil peroxidase (EPO) activity, suitable for bronchoalveolar lavage (BAL) analysis. A significant 2.9-fold (P < 0.01) increase in bronchial reactivity to histamine was observed at 6 h after allergen exposure, which was associated with a 2.9-fold increase in the number of eosinophils (P < 0.05) and a 6.7-fold increase in EPO activity (P < 0.01) in the BAL fluid. At 24 h after allergen exposure the bronchial reactivity to histamine was lower (1.7-fold), but still significantly enhanced (P < 0.01). By contrast, the number of eosinophils was further increased compared with 6 h after provocation (3.8-fold, P < 0.05), while the EPO activity remained stable at 6 h levels. The number of eosinophils was significantly correlated with EPO activity at 6 h (r = 0.62; P < 0.05), but not at 24 h after provocation. No significant correlation was observed between the number of eosinophils in the BAL fluid and BHR to histamine at either time point.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Muscarinic M2 receptors do not participate in the functional antagonism between methacholine and isoprenaline in guinea pig tracheal smooth muscle.

We investigated whether muscarinic M2 receptors, known to inhibit adenylyl cyclase activity in airway smooth muscle, also inhibit isoprenaline-induced relaxation of guinea pig tracheal smooth muscle, as has recently been described for the dog (Fernandes et al., 1992, J. Pharmacol. Exp. Ther. 262, 119). Smooth muscle strips were contracted with various concentrations of methacholine or histamine (which served as a control) in the absence or presence of the M2-selective muscarinic receptor antagonist, gallamine (30 microM), and cumulative isoprenaline-relaxation curves were obtained. It was found that muscarinic M2 receptor blockade had no significant effect on isoprenaline pD2 and Emax values, neither with histamine nor with methacholine. The results show that, in guinea pig trachea, muscarinic M2 receptors do not significantly influence the functional antagonism of cholinergic smooth muscle contraction by isoprenaline.

Animals↗
PubMed1993

Lack of coupling of muscarinic receptors to phosphoinositide metabolism and adenylyl cyclase in human lymphocytes and polymorphonuclear leukocytes: studies in healthy subjects and allergic asthmatic patients.

A change in muscarinic receptor-induced phosphoinositide (PI) metabolism or inhibition of adenylyl cyclase activity could play a role in cholinergic hyperresponsiveness in patients with asthma. In the present study, we considered the possibility of using peripheral blood lymphocytes or polymorphonuclear leukocytes (PMN) as easily accessible models to investigate this hypothesis. Previous studies have indicated the presence of muscarinic binding sites on these cells; however, their transduction mechanisms are still unclear. We found that neither lymphocytes nor PMN from healthy donors, nor lymphocytes from allergic asthmatic patients accumulated inositol phosphates after stimulation with methacholine, whereas positive responses were found for phytohemagglutinin (PHA) in the lymphocytes and for formyl-methionyl-leucyl-phenyl-alanine in the PMN. Normal basal and PHA-stimulated inositol phosphates levels were found in the lymphocytes of the patients. Both levels were significantly enhanced after allergen challenge, indicating that activation of PI metabolism could play a role in the immune response of these cells. Since methacholine was also unable to inhibit adenylyl cyclase activity in both lymphocytes and PMN, we reevaluated the presence of muscarinic binding sites on these cells. Radioligand binding studies with the hydrophilic ligand [3H]-N-methyl-scopolamine surprisingly showed only a very small population of high affinity binding sites on lymphocytes (Bmax 57-127 sites/cell; Kd 45-133 pM), while no high affinity sites could be detected on PMN. The results indicate that leukocytes are not a suitable model to investigate the muscarinic receptor function in relation to bronchial asthma.

Adenylyl Cyclases↗
PubMed1992

A novel method to assess airway function parameters in chronically instrumented, unrestrained guinea-pigs.

A new method has been developed to measure airway functions in unanaesthetized, unrestrained guinea-pigs. The technique utilizes a specially designed pneumotachograph that is placed inside the trachea, and a saline-filled balloon, placed inside the pleural cavity. The pneumotachograph consists of a stainless steel cylinder with coaxial and perpendicular tubes attached to it, measuring the total pressure and the lateral pressure in the trachea, respectively. Via air-filled silicon conducting tubes, subcutaneously driven and permanently attached to the neck of the animal, the pressures are fed into a differential pressure transducer, yielding a pressure difference proportional to the airflow in the trachea. Via a saline-filled tubing, the pleural balloon is similarly attached to the neck of the animal, and pleural pressure (Ppl) is measured using a second pressure transducer. These data permit calculation of airway functions in conscious, unstressed animals. Control values for airway resistance (RAW), Ppl, tidal volume and respiratory frequency are all in the range of results reported previously for this species. A very significant correlation between RAW and Ppl (P < 0.001) was observed, indicating that sole Ppl-measurement can be used as a relatively simple and sensitive method to assess bronchial obstructive reactions in unrestrained guinea-pigs. Using a specially designed provocation cage, which allowed the animals to remain in a stress-free, unrestrained condition, the method has been successfully applied for the assessment of the dose-dependent bronchoconstrictor sensitivity to histamine as well as to allergen-induced early and late phase airway reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1990

Characterization of presynaptic vascular muscarinic receptors inhibiting endogenous noradrenaline overflow in the portal vein of the freely moving rat.

1. In the portal vein of permanently cannulated, freely moving, unanaesthetized rats, methacholine (MCh) is able to inhibit the electrically-evoked endogenous noradrenaline (NA) overflow. This inhibition is mediated by presynaptic inhibitory muscarinic heteroreceptors. 2. By use of pirenzepine, 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP) and AF-DX 116 as M1-, M3-, and M2-selective antagonists respectively, the MCh (0.1 microM)-induced inhibition of the electrically-evoked NA overflow could be reversed to the control stimulation value dose-dependently. 3. The potency order of the antagonists was: 4-DAMP greater than AF-DX 116 greater than pirenzepine, pIC50 values being 8.50, 7.96 and 7.01, respectively. 4. From these results it was concluded that the inhibitory presynaptic heteroreceptors in the portal vein of conscious unrestrained rats are of the cardiac M2-subtype.

Animals↗
PubMed1990

Characterization of the muscarinic receptor subtype involved in phosphoinositide metabolism in bovine tracheal smooth muscle.

1. The muscarinic receptor subtype involved in the methacholine-induced enhancement of phosphoinositide metabolism in bovine tracheal smooth muscle was identified by using the M2-selective antagonist AF-DX 116 and the M3-selective antagonist 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) methobromide, in addition to the M1-selective antagonist pirenzepine, in a classical Schild analysis. 2. All the antagonists shifted the methacholine dose-response curve to the right in a parallel and concentration-dependent fashion, yielding Schild plots with slopes not significantly different from unity. The pA2 values (6.94, 6.32 and 8.54 for pirenzepine, AF-DX 116 and 4-DAMP methobromide respectively) indicate that it is the M3 (smooth muscle/glandular), but not the M2 (cardiac) muscarinic receptor subtype, present in this tissue, that mediates phosphoinositide turnover, in accordance with our previous contractile studies. 3. The results provide additional evidence for the involvement of phosphoinositide turnover in the pharmacomechanical coupling between muscarinic receptor stimulation and contraction in (bovine tracheal) smooth muscle.

Animals↗
PubMed1990

Role of phosphoinositide metabolism in human bronchial smooth muscle contraction and in functional antagonism by beta-adrenoceptor agonists.

The aim of the present investigation was to study in human bronchial smooth muscle (1) the relationship between methacholine and histamine-induced inositol phosphate (IP) production and contraction, (2) the influence of increasing concentrations of methacholine and histamine on the relaxation (pD2 and Emax) by isoproterenol (functional antagonism), and (3) the relation between IP production by methacholine and histamine and the changes of pD2 and Emax values of isoproterenol-induced relaxation. Methacholine and histamine were full agonists in contracting human bronchial smooth muscle, with pD2 values of 6.01 +/- 0.18 and 6.07 +/- 0.04, respectively. With IP production, however, pD2 values of 4.90 +/- 0.06 for methacholine and 5.15 +/- 0.16 for histamine were obtained, indicating a considerable reserve of PI metabolism for contraction. With increasing concentrations of histamine and methacholine (to 1 and 0.1 mM, respectively), subsequently performed dose-relaxation curves with isoproterenol showed decreasing values of pD2 (from 8.25 +/- 0.20 to 7.28 +/- 0.28) and Emax (from 100% to 56.7 +/- 12.4%). No differences were observed between methacholine and histamine in this respect. A significant correlation was found between IP production induced by the various concentrations of methacholine and histamine and the reduction of isoproterenol pD2 and Emax values. The results strongly suggest that PI metabolism may play an important role in the reduced efficacy of beta-adrenoceptor agonists to induce bronchodilation during active and severe asthma.

Aged↗
PubMed1989

Muscarinic receptors in human airway smooth muscle are coupled to phosphoinositide metabolism.

In the present study we investigated whether muscarinic receptors in human airway smooth muscle are coupled to phosphoinositide metabolism as a possible transduction mechanism of contraction. Using isolated bronchial smooth muscle preparations, we found that the muscarinic agonist methacholine caused a time- and concentration-dependent accumulation of inositol phosphates in the presence of lithium, an effect which could be inhibited by atropine. Apart from its physiological significance, this finding may have great relevance for the biochemical investigation of cholinergic hyperresponsiveness in the airways of asthmatic patients.

Atropine↗