PAF-induced contraction of canine trachea mediated by 5-hydroxytryptamine in vivo

1989 ◽  
Vol 66 (2) ◽  
pp. 638-643 ◽  
Author(s):  
T. M. Murphy ◽  
N. M. Munoz ◽  
J. Moss ◽  
J. S. Blake ◽  
M. M. Mack ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Dose Response ◽  
Contractile Response ◽  
Platelet Activating Factor ◽  
Smooth Muscle Contraction ◽  
Active Tension ◽  
Response Curves ◽  
Arteriovenous Difference

We studied the secretory correlates of tracheal smooth muscle contraction caused by platelet-activating factor (PAF) in nine mongrel dogs in vivo. In five dogs, dose-response curves were generated by rapid intra-arterial injection of 10(-10) to 10(-6) mol PAF into the isolated tracheal circulation; tracheal contractile response was measured isometrically in situ. To examine the mechanism by which PAF elicits contraction of canine trachealis, concentrations of serotonin (5-HT) and histamine were assayed in the venous effluent as the arteriovenous difference (AVd) in mediator concentration across the airway for each level of contraction. PAF caused dose-related active tracheal tension to a maximum of 37.2 +/- 5.4 g/cm (10(-6) mol PAF). The AVd in 5-HT increased linearly from 0.20 +/- 0.05 (10(-9) mol PAF) to 3.5 +/- 0.3 ng/ml (10(-6) mol PAF) (P less than 0.005). In contrast, the AVd in histamine was insignificant and did not change with increasing doses of PAF. A positive correlation was obtained between the AVd in 5-HT and active tracheal tension (r = 0.92, P less than 0.001); there was no correlation between AVd in histamine and active tension (r = -0.16). PAF-induced parasympathetic activation was not mediated by 5-HT; contraction elicited by exogenous 5-HT was not affected by muscarinic blockade. We conclude that nonparasympathetically mediated contraction elicited acutely by PAF in dogs results at least in part from secondary release of serotonin and is not mediated by histamine.

Parasympathetic involvement in PAF-induced contraction in canine trachealis in vivo

1987 ◽  
Vol 62 (2) ◽  
pp. 599-605 ◽  
Author(s):  
A. R. Leff ◽  
S. R. White ◽  
N. M. Munoz ◽  
K. J. Popovich ◽  
T. Shioya ◽  
...  
Keyword(s):  
Dose Response ◽  
Multiple Dose ◽  
Contractile Response ◽  
Platelet Activating Factor ◽  
Smooth Muscle Contraction ◽  
Active Tension ◽  
Maximal Contraction ◽  
Response Curves ◽  
Parasympathetic Nerves

We studied the contractile response elicited by platelet-activating factor (PAF) administered intra-arterially into the tracheal circulation of 34 dogs in vivo. A method that avoided tachyphylaxis encountered in prior investigations was developed for isometric measurement of multiple dose-response effects. PAF was a very potent contractile agent; active tension was elicited with 10(-11) mol ia PAF. To determine the mechanism by which contraction was induced, dose-response curves were generated in groups of five animals each treated with either 0.5 mg/kg (approximately 1.5 X 10(-5) mol) iv + 10(-3) mg/kg (3 X 10(-8) mol) ia atropine, 5 mg/kg iv indomethacin (INDO), or 7.5 mg/kg iv hexamethonium (HEX). After pretreatment with atropine, contraction still was elicited with 10(-11) mol ia PAF. However, maximal contraction was only 16.2 +/- 2.74 g/cm (vs. 35.7 +/- 5.74 g/cm for untreated controls; P less than 0.02). The dose at which maximal contraction was elicited after atropine was 10(-7) mol ia (vs. 1.9 X 10(-9) mol for controls; P less than 0.001). Pretreatment with INDO caused minimal attenuation, and HEX had no effect on the response elicited by ia PAF. We demonstrate a method for assessing the effects of PAF in central airways that avoids tachyphylaxis and permits dose-response studies in the same animal. We also demonstrate that PAF is an extremely potent mediator that elicits tracheal smooth muscle contraction at least in part by postganglionic activation of parasympathetic nerves. A direct contractile effect of PAF which is not related to secretion of products of the cyclooxygenase pathway is also suggested.

Histamine tachyphylaxis in canine airways despite prostaglandin synthesis inhibition

1988 ◽  
Vol 65 (5) ◽  
pp. 1944-1949 ◽  
Author(s):  
P. J. Antol ◽  
S. J. Gunst ◽  
R. E. Hyatt
Keyword(s):  
Smooth Muscle ◽  
Dose Response ◽  
Prostaglandin Synthesis ◽  
Response Curves ◽  
Synthesis Inhibition ◽  
High Concentrations ◽  
Alpha Chloralose ◽  
Prostaglandin Synthesis Inhibitors

Tachyphylaxis to aerosolized histamine was studied in dogs anesthetized with thiamylal after pretreatment with prostaglandin synthesis inhibitors. Three consecutive histamine dose-response curves were obtained in nine dogs pretreated with 5 mg/kg indomethacin; two of these nine were also pretreated with 10 mg/kg indomethacin. Seven of the nine dogs were pretreated with 4 mg/kg sodium meclofenamate; four of these seven were also pretreated with 12 mg/kg. All dogs had tachyphylaxis at high concentrations of histamine regardless of inhibitor used. Pretreatment with indomethacin while the dogs were under alpha-chloralose-urethan anesthesia gave similar results. Histamine tachyphylaxis was also studied both in the presence and in the absence of indomethacin in tracheal smooth muscle strips obtained from seven additional dogs. A decrease in the median effective dose to histamine was observed in the indomethacin-treated strips, but tachyphylaxis to histamine remained. We conclude that prostaglandin synthesis inhibition does not reverse histamine tachyphylaxis either in vivo or in vitro. Thus the mechanism of histamine tachyphylaxis remains unexplained.

In vivo evaluation of the effectiveness of bronchial thermoplasty with computed tomography

2005 ◽  
Vol 98 (5) ◽  
pp. 1603-1606 ◽  
Author(s):  
Robert H. Brown ◽  
William Wizeman ◽  
Christopher Danek ◽  
Wayne Mitzner
Keyword(s):  
Computed Tomography ◽  
Smooth Muscle ◽  
Dose Response ◽  
Response Curves ◽  
High Resolution Computed Tomography ◽  
In Vivo Evaluation ◽  
Airway Narrowing ◽  
Bronchial Thermoplasty ◽  
Dose Response Curves

A recent study has reported that the application of thermal energy delivered through a bronchoscope (bronchial thermoplasty) impairs the ability of airway smooth muscle to shorten in response to methacholine (MCh)(Danek CJ, Lombard CM, Dungworth DL, Cox PG, Miller JD, Biggs MJ, Keast TM, Loomas BE, Wizeman WJ, Hogg JC, and Leff AR. J Appl Physiol 97: 1946–1953, 2004). If such a technique is successful, it has the potential to serve as a therapy to attenuate airway narrowing in asthmatic subjects regardless of the initiating cause that stimulates the smooth muscle. In the present study, we have applied high-resolution computed tomography to accurately quantify the changes in airway area before and after a standard MCh aerosol challenge in airways treated with bronchial thermoplasty. We studied a total of 193 airways ranging from 2 to 15 mm in six dogs. These were divided into treated and control populations. The MCh dose-response curves in untreated airways and soon-to-be-treated airways were superimposable. In contrast, the dose-response curves in treated airways were shifted upward at all points, showing a significantly decreased sensitivity to MCh at both 2 and 4 wk posttreatment. These results thus show that treated airways have significantly increased luminal area at any dose of inhaled MCh compared with untreated airways. The work in this study thus supports the underlying concept that impairing the smooth muscle may be an effective treatment for asthma.

Effect of resting smooth muscle length on contractile response in resistance airways

1987 ◽  
Vol 62 (2) ◽  
pp. 711-717 ◽  
Author(s):  
T. Shioya ◽  
N. M. Munoz ◽  
A. R. Leff
Keyword(s):  
Smooth Muscle ◽  
Contractile Response ◽  
Muscle Length ◽  
Transpulmonary Pressure ◽  
Bolus Administration ◽  
Response Curves ◽  
Fifth Generation ◽  
Bolus Intravenous Injection ◽  
Residual Capacity

We studied the effect of resting smooth muscle length on the contractile response of the major resistance airways (generations 0–5) in 18 mongrel dogs in vivo using tantalum bronchography. Dose-response curves to 10(-10) to 10(-7) mol/kg methacholine (MCh) were generated [at functional residual capacity (FRC)] by repeated intravenous bolus administration using tantalum bronchography after each dose. Airway constriction varied substantially with dose-equivalent stimulation and varied sequentially from trachea (8.8 +/- 2.2% change in airway diam) to fifth-generation bronchus (49.8 +/- 3.0%; P less than 0.001). Length-tension curves were generated for each airway to determine the airway diameter (i.e., resting in situ smooth muscle length) at which maximal constriction was elicited using bolus intravenous injection of 10(-8) mol/kg MCh. A Frank-Starling relationship was obtained for each airway; the transpulmonary pressure at which maximal constriction was elicited increased progressively from 2.50 +/- 1.12 cmH2O for trachea (approximately FRC) to 18.3 +/- 1.05 cmH2O for fifth-generation airways (approximately 50% TLC) (P less than 0.001). A similar relationship was obtained when change in airway diameter was plotted as a function of airway radius. We demonstrate substantial heterogeneity in the lung volumes at which maximal constriction is elicited and in distribution of parasympathomimetic constriction within the first few generations of resistance bronchi. Our data also suggest that lung hyperinflation may lead to augmented airway contractile responses by shifting resting smooth muscle length toward optimum resting smooth muscle length.

Measurement of airway response by isometric and nonisometric techniques in situ

1982 ◽  
Vol 52 (5) ◽  
pp. 1363-1367 ◽  
Author(s):  
A. R. Leff ◽  
N. M. Munoz ◽  
B. Alderman
Keyword(s):  
Smooth Muscle ◽  
Dose Response ◽  
Contractile Response ◽  
Muscle Tone ◽  
Dynamic Compliance ◽  
Isometric Tension ◽  
Pulmonary Resistance ◽  
Airway Response ◽  
Anesthetized Dogs

Because isometric systems differ substantially from methods of measuring airway smooth muscle tone that depend on airway diameter, we determined the sensitivity and significance of data derived from these different methods in 20 anesthetized dogs. The airway contractile response was measured directly from an isometric tracheal segment in situ and simultaneously as pulmonary resistance (RL) and dynamic compliance (Cdyn). The contractile response to intravenous (iv) methacholine (MC) (2.6 X 10(-11) to 2.6 X 10(-6) mol/kg) and norepinephrine (NE) (1.2 X 10(-11) to 1.2 X 10(-6) mol/kg) was measured in dose-response studies of beta-blocked and ganglion-blocked animals. A statistically significant change in isometric tracheal tension was first observed at 2.6 X 10(-10) mol/kg iv MC and 1.2 X 10(-9) mol/kg iv NE. Statistically significant changes in Cdyn and RL did not occur at doses less than 10(-8) mol/kg for either agonist. Substantial increase in isometric tracheal tension (greater than 10 g force/cm) occurred before any change in RL or Cdyn. These finding indicate that change in isometric tension reflects parallel changes in RL and Cdyn. For NE and MC, tracheal tension is a more sensitive and selective measurement of airway contraction than RL or Cdyn.

Epithelial augmentation of trachealis contraction caused by major basic protein of eosinophils

1989 ◽  
Vol 66 (4) ◽  
pp. 1867-1873 ◽  
Author(s):  
J. D. Brofman ◽  
S. R. White ◽  
J. S. Blake ◽  
N. M. Munoz ◽  
G. J. Gleich ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Basic Protein ◽  
Tracheal Smooth Muscle ◽  
Active Tension ◽  
Major Basic Protein ◽  
Human Eosinophil ◽  
Control Segment ◽  
Eosinophil Granule

We studied the effect of epithelial removal and intraepithelial administration of human eosinophil granule major basic protein (MBP) on the contraction of underlying canine tracheal smooth muscle in 23 dogs in vivo. A dual in situ tracheal preparation was utilized that allowed sharp excision of epithelium. The response to intra-arterial acetylcholine (ACh) was augmented substantially in five dogs receiving 200 micrograms MBP by intraepithelial instillation. Active tension elicited by 10(-8) mol intra-arterial ACh was 34.0 +/- 2.2 g/cm before and 46.1 +/- 2.6 g/cm 30 min after MBP (P less than 0.002). There was no change in active tension in the control segment in the same dogs after intraepithelial instillation of vehicle only (34.7 +/- 3.2 vs. 34.4 +/- 2.3 g/cm; P = NS). Instillation of MBP directly into the subepithelial tracheal smooth muscle did not alter contraction. To assess whether this augmentation was caused by inhibition of an epithelial-derived relaxant factor, additional studies were performed in nine other dogs in which the epithelium was excised discretely from one of the two tracheal segments. No significant differences in contractile response to ACh or relaxation response to isoproterenol were observed at 2, 15, 30, or 60 min after epithelial excision. We demonstrate that intraepithelial administration of MBP augments the contraction of underlying canine tracheal smooth muscle elicited by ACh. This augmentation is a direct effect of MBP and does not require antagonism of epithelial inhibition.

Neutral endopeptidase modulates neurotensin-induced airway contraction

1989 ◽  
Vol 66 (5) ◽  
pp. 2338-2343 ◽  
Author(s):  
T. D. Djokic ◽  
D. J. Dusser ◽  
D. B. Borson ◽  
J. A. Nadel
Keyword(s):  
Smooth Muscle ◽  
Serine Proteases ◽  
Neutral Endopeptidase ◽  
Smooth Muscle Contraction ◽  
Response Curves ◽  
Terminal Fragment ◽  
Carboxypeptidase N

To determine the role of endogenous neutral endopeptidase (NEP) (also called enkephalinase, EC 3.4.24.11) in regulating neurotensin-induced airway contraction, we used phosphoramidon, a specific NEP inhibitor, in the guinea pig. In studies in vitro, neurotensin and the COOH-terminal fragment neurotensin-(8–13) contracted strips of bronchial smooth muscle in a concentration-dependent fashion (P less than 0.001). In contrast, the NH2-terminal fragment neurotensin-(1–11) and the COOH-terminal fragment neurotensin-(12–13), the main fragments of neurotensin hydrolysis by NEP, had no effect. Phosphoramidon (10(-5) M) did not change resting tension but shifted the concentration-response curves to neurotensin to lower concentrations (P less than 0.001), whereas inhibitors of kininase II, aminopeptidases, serine proteases, and carboxypeptidase N were without effect. Removing the epithelium increased the contractile response to neurotensin (P less than 0.001), and phosphoramidon further increased the response to neurotensin in these tissues (P less than 0.001). Similar results were obtained in studies in vivo using aerosolized neurotensin and phosphoramidon. These results suggest that endogenous NEP in the airways modulates the effects of neurotensin on airway smooth muscle contraction by inactivating the peptide.

A limited rote for leukotrienes and platelet-activating factor in food protein induced jejunal smooth muscle contraction in sensitized rats

1991 ◽  
Vol 69 (12) ◽  
pp. 1841-1846 ◽  
Author(s):  
R. B. Scott ◽  
M. Maric
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Receptor Antagonist ◽  
Contractile Response ◽  
Platelet Activating Factor ◽  
Smooth Muscle Contraction ◽  
Food Protein ◽  
Lipoxygenase Inhibitor ◽  
Leukotriene Receptor ◽  
Web 2086

To determine whether the release of newly formed mediators such as the peptidoleukotrienes and platelet-activating factor might modulate the food protein induced jejunal smooth muscle contraction observed in sensitized rats, Hooded–Lister rats were sensitized by injection of ovalbumin (10 μg i.p.) and controls were sham sensitized with saline. Fourteen days later the contractility of longitudinally (n = 9) and circularly (n = 9) oriented jejunal segments (mucosa intact) were examined in standard tissue baths in response to antigen, leukotrienes, and platelet-activating factor alone and in the presence of a specific leukotriene receptor antagonist (MK-571), a 5-lipoxygenase inhibitor (L651,392), and a platelet-activating factor receptor antagonist (WEB 2086). Although the responses of control and sensitized tissues to stretch and 10−4 M bethanechol were similar, only sensitized tissues contracted in response to antigen (1 mg/mL). MK-571 (10−5 M) reduced or significantly inhibited the contractile response of sensitized longitudinally and circularly oriented tissues to 10−7 M leukotrienes C4, D4, or E4, but neither L651,392 (10−4 M) nor MK-571 (10−5 M) significantly reduced the contractile response of sensitized tissues to antigen challenge. WEB 2086 (10−4 M) significantly (p < 0.01) reduced the contractile response of sensitized longitudinally and circularly oriented tissues to 10−7 M platelet-activating factor but did not significantly alter the response to antigen in longitudinally (45% of control, p = 0.14) or circularly (118% of control, ns) oriented jejunal smooth muscle. In this model leukotrienes and platelet-activating factor play an insignificant role in modulating food protein induced jejunal smooth muscle contraction in intestinal anaphylaxis.Key words: leukotrienes, platelet-activating factor, smooth muscle, anaphylaxis, food allergy.

Thrombopoietin responsiveness reflects the number of doublings undergone by megakaryocyte progenitors

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2291-2298 ◽  
Author(s):  
Jean-Michel Paulus ◽  
Najet Debili ◽  
Frédéric Larbret ◽  
Jack Levin ◽  
William Vainchenker
Keyword(s):  
Dose Response ◽  
Receptor Density ◽  
Response Curves ◽  
Age Model ◽  
Normal Human ◽  
The Mean ◽  
Dose Response Curves

Abstract To assess the variation of thrombopoietin (TPO) responsiveness associated with megakaryocyte (MK) progenitor amplification, TPO dose-response curves were obtained for normal human, single-cell plated CD34+CD41+ cells. The number of MKs per well was determined in situ and expressed as number of doublings (NbD). Dose-response curves of the mean frequency of clones of each size versus log TPO concentration showed highly significant differences in the TPO concentration needed for half-maximum generation of clones of different sizes (TPO50): 1.89 ± 0.51 pg/mL for 1 MK clones; 7.75 ± 0.81 pg/mL for 2 to 3 MK clones; 38.5 ± 5.04 pg/mL for 4 to 7 MK clones, and 91.8 ± 16.0 pg/mL for 8 to 15 MK clones. These results were consistent with a prediction of the generation-age model, because the number of previous doublings in vivo was inversely correlated with the number of residual doublings in vitro. TPO responsiveness decreased in vitro by a factor of 3.5 per doubling, reflecting the recruitment of progressively more ancestral progenitors. In support of this hypothesis, the more mature CD34+CD41+CD42+ cell fraction had a lower TPO50 (P &lt; .001), underwent fewer NbD (P &lt; .001), and expressed a 2.8-fold greater median Mpl receptor density (P &lt; .001) than the CD34+CD41+CD42– fraction. Progenitors that have completed their proliferative program have maximum factor responsiveness and are preferentially induced to terminal differentiation.

Ca2+ utilization in guinea pig ileal longitudinal smooth muscle in response to a series of muscarinic agonists

1979 ◽  
Vol 57 (12) ◽  
pp. 1375-1380 ◽  
Author(s):  
L. B. Rosenberger ◽  
D. J. Triggle
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Dose Response ◽  
Mechanical Response ◽  
Contractile Response ◽  
Muscarinic Agonists ◽  
Response Curves ◽  
Partial Agonists ◽  
Ca Uptake ◽  
Dose Response Curves

45Ca uptake associated with the mechanical responses to a series of muscarinic agonists including carbachol, cis-2-methyl-4-dimethylaminomethyl-1,3-dioxolane methiodide, and three related 1,3-dioxolanes, including full and partial agonists, has been measured. Generally good agreement is found between the dose–response curves for 45Ca uptake and mechanical response, indicating that the processes of 45Ca entry, believed to be mediated through Ca2+ channels, and contractile response are closely linked. Consistent with this, partial agonists show (relative to full agonists) a reduced 45Ca uptake. The dose–response curves for carbachol-mediated contractile response and 45Ca uptake are compared with available literature data for carbachol action in the guinea pig ileal smooth muscle including binding, depolarization, and phosphatidylinositol turnover.

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