Biomedical subjects

A Ben-Jebria

Publications and source records attributed to A Ben-Jebria.

At least 19 recordsLinked to original sources

PubMed2001

Longitudinal distribution of ozone and chlorine in the human respiratory tract: simulation of nasal and oral breathing with the single-path diffusion model.

In the single-path model of the respiratory system, gas transport occurs within a conduit of progressively increasing cross-sectional and surface areas by a combination of flow, longitudinal dispersion, and lateral absorption. The purpose of this study was to use bolus inhalation data previously obtained for chlorine (Cl(2)) and for ozone (O(3)) to test the predictive capability of the single-path model and to adjust input parameters for applying the model to other exposure conditions. The data, consisting of uptake fraction as a function of bolus penetration volume, were recorded on 10 healthy nonsmokers breathing orally as well as nasally at alternative air flows of 150, 250, and 1000 ml/s. By employing published data for airway anatomy, gas-phase dispersion coefficients, and gas-phase mass transfer coefficients while neglecting diffusion limitations in the mucus phase, the single-path model was capable of predicting the uptake distribution for O(3) but not the steeper distribution that was observed for Cl(2). To simultaneously explain the data for these two gases, it was necessary to increase gas-phase mass transfer coefficients and to include a finite diffusion resistance of O(3) within the mucous layer. The O(3) reaction rate constants that accounted for this diffusion resistance, 2 x 10(6) s(-1) in the mouth and 8 x 10(6) s(-1) in the nose and lower airways, were much greater than previously reported reactivities of individual substrates found in mucus.

Administration, Inhalation↗

PubMed2001

Ozone absorption in the human nose during unidirectional airflow.

This study addresses the effect of gas flow rate and ozone (O(3)) concentration on the uptake of this air pollutant in the nose. A nasal exposure system was developed in which a constant flow of humidified air (V) containing a constant concentration of O(3) (C(inlet)) entered one nostril and then exited the other nostril while a subject closed the velopharyngeal aperture. Experiments were conducted on 10 healthy nonsmokers for whom O(3) concentration was measured at the inlet nostril and the outlet nostril to determine the fraction of inhaled O(3) that was absorbed into the nasal mucosa (Lambda(nose)). Lambda(nose) decreased from 0.80 +/- 0.02 to 0.33 +/- 0.02 (SE) when V was increased from 3 to 15 l/min and C(inlet) was fixed at 0.4 ppm. Analysis of these data with a mathematical model indicated that O(3) uptake was limited by diffusion reaction through mucus, rather than by convective diffusion through the respired gas. A small decrease in Lambda(nose) from 0.36 +/- 0.02 to 0.32 +/- 0.01 was also observed when C(inlet) was increased from 0.1 to 0.4 ppm at a fixed V of 15 l/min. This may have been due to nonlinear reaction kinetics between O(3) and reactive substrates in mucus or an active response by a physiological process such as mucus secretion or transepithelial water influx.

Absorption↗

PubMed2000

Ozone uptake in the intact human respiratory tract: relationship between inhaled dose and actual dose.

Inhaled concentration (C), minute volume (MV), and exposure duration (T) are factors that may affect the uptake of ozone (O(3)) within the respiratory tract. Ten healthy adult nonsmokers participated in four sessions, inhaling 0.2 or 0.4 ppm O(3) through an oral mask while exercising continuously to elicit a MV of 20 l/min for 60 min or 40 l/min for 30 min. In each session, fractional absorption (FA) was determined on a breath-by-breath basis as the ratio of O(3) uptake to the inhaled O(3) dose. The mean +/- SD value of FA for all breaths was 0.86 +/- 0.06. Although C, MV, and T all had statistically significant effects on FA (P < 0.0001, P = 0.004, and P = 0.026, respectively), the magnitudes of these effects were small compared with intersubject variability. For an average subject, a 0. 05 change in FA would require that C change by 1.3 ppm, MV change by 46 l/min, or T change by 1.7 h. It is concluded that inhaled dose is a reasonable surrogate for the actual dose delivered to a particular subject during O(3) exposures of <2 h, but it is not a reasonable surrogate when comparisons are made between individuals.

Absorption↗

PubMed1999

Large porous particles for sustained protection from carbachol-induced bronchoconstriction in guinea pigs.

PURPOSE: To determine whether a new formulated albuterol aerosol could sustain inhibition to bronchoconstriction for approximately one day in guinea pigs challenged with carbachol. METHODS: Large and porous particles, comprising a combination of endogenous or FDA-approved excipients and albuterol sulfate, were prepared by spray drying using a NIRO portable spray drier. The anesthetized animals inhaled 5 mg of large porous or small nonporous particles by forced ventilation via cannulae inserted in the lumen of their exposed tracheae. At regular intervals over a period of 36 hours after drug delivery, airway resistance was determined in response to carbachol challenge dose. RESULTS: Whereas inhalation of small nonporous albuterol particles protected from the carbachol-induced bronchoconstriction for up to 5 hours, inhalation of large porous albuterol particles produced a significant inhibition of carbachol-induced bronchoconstriction for at least 16 hours. CONCLUSIONS: The absence of substantial side effects, verified over a period of 24 hours by evaluating cardio-respiratory parameters as well as pulmonary inflammation, supports the utility of large porous albuterol particles for sustained therapies in asthma and other types of lung disease.

Administration, Inhalation↗

PubMed1999

Inhalation of estradiol for sustained systemic delivery.

Large porous estradiol particles were formulated by spray drying estradiol in combination with various U.S. Food and Drug Administration (FDA)-approved or endogenous excipients. The powders were characterized in terms of their geometrical size, mass density, and aerosolization properties. Small nonporous particles were also prepared using the same excipients and were physically characterized to insure that they possessed a similar mean aerodynamic size as the large porous particles. The two powders were aerosolized into the lungs of rats via an endotracheal tube or subcutaneously injected as a control to assess relative bioavailability. Two different large porous particle formulations were found to produce elevated systemic estradiol concentrations upon inhalation for approximately 5 days, with relative bioavailabilities of 59.7% and 86.0%. Systemic estradiol concentrations following inhalation of two different small nonporous particle powders remained elevated for only approximately 1 day, with relative bioavailabilities of 18.3% and 38.7%. Bronchoalveolar lavage was performed up to 96 hours after inhalation of porous and nonporous estradiol powders. Small changes in neutrophil and macrophage populations were observed following inhalation of both the porous and nonporous powders.

Administration, Inhalation↗

PubMed1998

Recent advances in pulmonary drug delivery using large, porous inhaled particles.

The ability to deliver proteins and peptides to the systemic circulation by inhalation has contributed to a rise in the number of inhalation therapies under investigation. For most of these therapies, aerosols are designed to comprise small spherical droplets or particles of mass density near 1 g/cm3 and mean geometric diameter between approximately 1 and 3 micron, suitable for particle penetration into the airways or lung periphery. Studies performed primarily with liquid aerosols have shown that these characteristics of inhaled aerosols lead to optimal therapeutic effect, both for local and systemic therapeutic delivery. Inefficient drug delivery can still arise, owing to excessive particle aggregation in an inhaler, deposition in the mouth and throat, and overly rapid particle removal from the lungs by mucocilliary or phagocytic clearance mechanisms. To address these problems, particle surface chemistry and surface roughness are traditionally manipulated. Recent data indicate that major improvements in aerosol particle performance may also be achieved by lowering particle mass density and increasing particle size, since large, porous particles display less tendency to agglomerate than (conventional) small and nonporous particles. Also, large, porous particles inhaled into the lungs can potentially release therapeutic substances for long periods of time by escaping phagocytic clearance from the lung periphery, thus enabling therapeutic action for periods ranging from hours to many days.

Administration, Inhalation↗

PubMed1997

Large porous particles for pulmonary drug delivery.

A new type of inhalation aerosol, characterized by particles of small mass density and large size, permitted the highly efficient delivery of inhaled therapeutics into the systemic circulation. Particles with mass densities less than 0.4 gram per cubic centimeter and mean diameters exceeding 5 micrometers were inspired deep into the lungs and escaped the lungs' natural clearance mechanisms until the inhaled particles delivered their therapeutic payload. Inhalation of large porous insulin particles resulted in elevated systemic levels of insulin and suppressed systemic glucose levels for 96 hours, whereas small nonporous insulin particles had this effect for only 4 hours. High systemic bioavailability of testosterone was also achieved by inhalation delivery of porous particles with a mean diameter (20 micrometers) approximately 10 times that of conventional inhaled therapeutic particles.

Administration, Inhalation↗

PubMed1997

Improvement of a respiratory ozone analyzer.

The breath-to-breath measurement of total respiratory ozone (O3) uptake requires monitoring O3 concentration at the airway opening with an instrument that responds rapidly relative to the breathing frequency. Our original chemiluminescent analyzer, using 2-methyl-2-butene as the reactant gas, had a 10% to 90% step-response time of 110 msec and a minimal detectable concentration of 0.018 parts per million (ppm) O3 (Ben-Jebria et al. 1990). This instrument was suitable for respiratory O3 monitoring during quiet breathing and light exercise. For this study, we constructed a more self-contained analyzer with a faster response time using ethylene as the reactant gas. When the analyzer was operated at a reaction chamber pressure of 350 torr, an ethylene-to-sample flow ratio of 4:1, and a sampling flow of 0.6 liters per minute (Lpm), it had a 10% to 90% step-response time of 70 msec and a minimal detectable concentration of 0.006 ppm. These specifications make respiratory O3 monitoring possible during moderate-to-heavy exercise. In addition, the nonlinear calibration and the carbon dioxide (CO2) interference exhibited by the original analyzer were eliminated. In breath-to-breath measurements in two healthy men, the fractional uptake of O3 during one minute of quiet breathing was comparable to the results obtained by using a slowly responding commercial analyzer with a quasi-steady material balance method (Wiester et al. 1996). In fact, fractional uptake was about 0.8 regardless of O3 exposure concentration (0.11 to 0.43 ppm) or ventilation rate (4 to 41 Lpm/m2).

Breath Tests↗

PubMed1996

Longitudinal distribution of ozone absorption in the lung: simulation with a single-path model.

A one-dimensional unsteady state diffusion model was used as a basis for simulating the absorption (lambda), breakthrough (V(B)), and dispersion (sigma2) of inhaled ozone boluses as a function of penetration (V(P)) into intact human lungs. The model idealized the respiratory system as a single equivalent tube with cross-sectional and surface areas that varied as a function of longitudinal position. Longitudinal gas transport in the lumen of the equivalent tube occurred by the joint action of bulk flow and a dispersion coefficient, D. Lateral absorption between respired gas and the tube wall was characterized by an overall mass transfer coefficient, K. By inputting published values of anatomic dimensions scaled to a 160-ml conducting airway volume, D values previously reported for inert insoluble gases, and K values equal to gas-phase transfer coefficients determined in physical lung models, a reasonable simulation of the lambda-V(P) distribution measured at a 250 ml/sec respiratory flow was obtained. Simulations of the corresponding V(B)-V(P) and sigma2-V(P) distributions both exhibited the correct shapes but underestimated the actual values. Although the addition of an estimated tissue resistance to K resulted in a poorer simulation of the data, an increase in conducting airway volume from a value of 160 ml estimated by the subjects' CO2 dead space to a value of 200 ml substantially improved the V(B)-V(P) and sigma2-V(P) simulations without sacrificing the quality of the lambda-V(P) simulation. We conclude that the inclusion of a tissue diffusion resistance is not necessary to properly simulate bolus inhalation data during quiet breathing, but a reliable measurement of conducting airway volume is crucial.

Absorption↗

PubMed1996

Longitudinal distribution of O3 absorption in the lung: gender differences and intersubject variability.

Because the National Ambient Air Quality Standard for ozone (O3) is intended to protect the most sensitive individuals in the general population, it is necessary to identify sources of intersubject variation in the exposure-dose-response cascade. We hypothesize that differences in lung anatomy can modulate exposure-dose relationships between individuals, and this results in differences between their responsiveness to O3 at a fixed exposure condition. During quiet breathing, the conducting airways remove the majority of inhaled O3, so the volume of this region should have an important impact on O3 dose distribution. Employing the bolus inhalation method, we measured the distribution of O3 absorption with respect to penetration volume (Vp), and using the Fowler single-breath N2 washout method, we determined the dead space volume (VD) in the lungs of 10 men and 10 women at a fixed respiratory flow of 250 ml/s. On average, the women absorbed O3 at smaller Vp than the men, and the women had smaller VD than the men. When expressed in terms of Vp/VD, the absorption distribution of the men and women was indistinguishable. Moreover, an interpretation of the O3 distribution in terms of an intrinsic mass transfer parameter (Ka) indicated that differences between the O3 dosimetry in all subjects, whether men or women, could be explained by a unique correlation with anatomic dead space: Ka (in s-1) = 610 VD-105 (in ml). Application of this result to measurements of O3 exposure response indicated that previously reported gender differences may be due to a failure in properly accounting for tissue surface within the conducting airways.

Absorption↗

PubMed1995

Acrolein-induced smooth muscle hyperresponsiveness and eicosanoid release in excised ferret tracheae.

Acrolein is a ubiquitous toxic air pollutant that can have adverse lung effects. To understand the mechanism governing airway reactivity in relation to acrolein uptake, in vitro experiments were conducted in which excised tracheae from ferrets were exposed for 1 hr to a unidirectional constant flow (100 ml/min) of an acrolein-in-air mixture at several concentrations (0-12.5 ppm). During exposure, acrolein uptake into the trachea was determined by a chromatographic analysis of gas samples taken at the entrance and at the exit of the trachea. Smooth muscle contractility in response to carbachol (CCh), acetylcholine (ACh), and potassium chloride (KCl) was measured following exposure, and eicosanoids released in the perfusate baths were assayed. The results indicate that the fractional uptake into an excised ferret trachea was strongly dependent on inlet concentration, implying that diffusion and reaction processes of acrolein in airway tissue are not linear. Only the low concentration of acrolein caused an increase of eicosanoid release from the exposed tracheae in the perfusate bath; it is possible that, at higher exposure concentration, the epithelium was sloughed off and most of the eicosanoids were lost. Although acrolein did not alter smooth muscle response to KCl, it did increase the contractile responses to CCh and ACh, suggesting an alteration in the pharmacomechanical but not the electromechanical coupling of ferret tracheal smooth muscle; therefore, it is more likely that this hyperresponsiveness occurs primarily by a mobilization of intracellular Ca2+ stores rather than by an increased influx of extracellular Ca2+ through voltage-dependent channels.

Acrolein↗

PubMed1994

Human airway smooth muscle responsiveness in neonatal lung specimens.

The mechanical activity of proximal airways isolated from human lung specimens obtained at autopsy from 11 neonates was studied in response to the following compounds: carbachol, histamine, potassium chloride (KCl), neurokinin A (NKA) (both in the presence and in the absence of the neutral endopeptidase inhibitor phosphoramidon) and isoproterenol. Isometric responses to the various concentrations of each of the compounds were expressed as both raw values of force normalized to smooth muscle cross-sectional area (SMCSA), i.e., muscle stress and percentages of the maximal response to acetylcholine. Maximal active muscle stress of human neonatal bronchi was induced by carbachol and averaged 95 +/- 25 mN/mm2 SMCSA (n = 8). The rank of maximal force induced by the contractile agonists was carbachol > histamine > KCl > NKA, and the rank of the concentration of drug producing one-half of the maximum effect (EC50) was NKA < carbachol < histamine < KCl. The EC50 value for isoproterenol was the lowest, although it generated the smallest mechanical response. When compared with results obtained under identical experimental conditions in the human adult lung, except for carbachol and isoproterenol, general trends were an increase in force generation with age and little changes in EC50 values. There was a decrease in carbachol-induced force with age, whereas the opposite was observed with isoproterenol. We conclude that most of the mechanisms that control airway tone in humans are already present in the neonate. Alterations in the response to agonists with the maturational process may have implications in the pharmacologic modulation of bronchial obstruction in neonates.

Carbachol↗

PubMed1994

Longitudinal distribution of ozone absorption in the lung: effects of respiratory flow.

In our previous work, we developed a bolus inhalation apparatus and measured the longitudinal distribution of ozone (O3) uptake in intact human lungs at a quiet respiratory flow of 250 ml/min. The objective of the present study was to determine the effect of alternative respiratory flows between 150 and 1,000 ml/s. Uptake was expressed as the O3 absorbed during a single breath relative to the amount of O3 in the inhaled bolus (lambda). Measurements of lambda were correlated with the penetration volume of the bolus into the respiratory tract (Vp). Vp in the range of 20-70 ml was considered to indicate upper airways (UA), the Vp interval of 70-180 ml was identified as lower conducting airways (CA), and Vp > 180 ml was associated with the respiratory air spaces (RA). During quiet oral breathing at 250 ml/s, lambda increased smoothly as Vp increased, with 50% of the inhaled O3 absorbed in the UAs and the remainder absorbed within the CAs such that no O3 reached the RAs. The effect of increasing the respiratory flow was to shift the lambda-Vp distribution distally such that significantly less O3 was absorbed in the UAs and CAs and some O3 reached the RAs. For example, at 1,000 ml/s, only 10% of the inhaled O3 was absorbed in UAs and 65% was absorbed in the CAs such that 25% reached the RAs.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗

PubMed1994

Longitudinal distribution of ozone absorption in the lung: comparison of nasal and oral quiet breathing.

Employing a bolus inhalation system, we noninvasively measured the fraction of inhaled ozone (O3) that is absorbed during a single breath (lambda) as a function of bolus penetration volume into the respiratory tract (Vp). During nasal breathing at a constant respiratory flow of 250 ml/s, lambda increased smoothly as Vp increased with 80% of the inhaled O3 absorbed in the upper airways and 90% absorbed at the distal end of the trachea. Oral breathing caused a distal shift of the lambda-Vp distribution to the extent that absorption in the upper airways was reduced to 50% and inhaled O3 was 90% absorbed only after a bolus reached the 13th bronchial generation. Therefore, an exercise-induced change from nasal to oral breathing can render the distal lung more susceptible to O3 damage because of an elevation in O3 dose. We also found that changing the peak inhaled bolus concentration over a 10-fold range of 0.4-4 ppm O3 did not affect the lambda-Vp distribution. This finding implies that the diffusion and chemical reaction dynamics that dictate O3 absorption are linear processes.

Absorption↗

PubMed1994

Human bronchial smooth muscle responsiveness after in vitro exposure to acrolein.

Human isolated bronchi obtained at thoracotomy from 42 patients were exposed to aqueous solutions of acrolein, and the resulting change in contractile responses was evaluated by measuring agonist cumulative concentration-response curves (CCRC). Contractile responses to carbachol were measured after a variety of exposure concentrations, from 0.01 to 3.0 microM, and at times from 5 to 60 min. The optimal condition to induce airway smooth muscle hyperresponsiveness was an exposure duration of 20 min at a concentration of 0.3 microM. The effect of acrolein exposure on human bronchial smooth muscle was also assessed by examining the contractile responses to potassium chloride (KCl), histamine, and neurokinin A (NKA) in both the absence and the presence of phosphoramidon. Although in vitro exposure of the human bronchus to 0.3 microM acrolein did not alter responses to KCl, it did increase the efficacy of carbachol and NKA without altering their potency. This concentration of acrolein also increased the contractile response to low concentrations of histamine and shifted the CCRC to the left. Pretreatment with phosphoramidon abolished the differential effect of acrolein on airway response to NKA. These results suggest that the mechanism of action of acrolein includes inactivation of airway neutral endopeptidase as well as alterations in the pharmacomechanical, but not the electromechanical, coupling of human bronchial smooth muscle.

Acrolein↗

PubMed1994

Noninvasive determination of respiratory ozone absorption: the bolus-response method.

Morphometric studies in animals exposed to ozone (O3), and mathematical simulations of O3 transport in human lungs indicate that O3 toxicity is focal in nature, causing tissue damage that is more pronounced in the proximal alveolar region (the proximal end of the respiratory airspaces in our compartment models) than in other airways. These findings suggest that the internal distribution of O3 uptake must be known in order to assess health risk reliably. In previous work (Ultman and Ben-Jebria 1990), we developed a fast-responding chemiluminescent O3 analyzer and a small-scale O3 generator, both of which are suitable for respiratory measurements. The objective of the current research was to integrate these instruments into a bolus inhalation system capable of noninvasively measuring the longitudinal distribution of O3 absorption in intact human lungs. With this system we aimed to carry out baseline experiments in healthy men during quiet oral breathing at a respiratory flow rate of 250 mL/sec, determine the effect of alternative respiratory flow rates between 150 and 1,000 mL/sec, compare the absorption distribution during quiet oral breathing with that during quiet nasal breathing, and ascertain the influence of a peak inspired concentration between 0.3 and 4.0 parts per million (ppm). Ozone uptake (lambda) was expressed as the amount of O3 absorbed during a single breath relative to the amount in the inhaled bolus. Measurements of lambda were correlated with the penetration volume (VP) of the bolus into the respiratory tract. Values of VP less than 70 mL were considered to be associated with the upper airways, values between 70 and 180 mL were associated with the lower conducting airways, and values greater than 180 mL were associated with the respiratory airspaces. During quiet oral breathing, lambda increased smoothly with VP, with 50% of the inhaled O3 absorbed in the upper airways and the balance absorbed within the lower conducting airways. This compares favorably with the results of direct-sampling methods, which have indicated that 40.4% of continuously inhaled O3 is removed by the extrathoracic airways (Gerrity et al. 1988). The effect of increasing the respiratory flow, which occurs when people exercise, was to shift the lambda-VP distribution distally so that significantly less O3 was absorbed in the upper airways and more reached the respiratory airspaces. Compared with oral breathing, nasal breathing caused a proximal shift in the lambda-VP distribution to the extent that absorption in the upper airways increased from 50% to 80%.(ABSTRACT TRUNCATED AT 400 WORDS)

Absorption↗

PubMed1993

Effect of in vitro exposure to acrolein on carbachol responses in rat trachealis muscle.

Isolated tracheal rings obtained from male Wistar rats 10 to 15 weeks old and weighing 300 to 400 g were exposed to aqueous solutions of acrolein, and the resulting change of smooth muscle contractility was evaluated by measuring the cumulative carbachol concentration-response curve. Using the product of acrolein concentration and time as a surrogate for the acrolein dose delivered to the smooth muscle cells, contractility measured after a variety of exposure concentrations from 0.01 to 3.0 microM and times from 5 to 60 min could be correlated in a dose-dependent manner. In the range of doses from 0.1 to 6 microM-min, relative contractility continuously increased from 0 to 50% above unexposed control values. At doses greater than 6 microM-min, the enhancement in contractility declined. This decline may have been due to cell damage or cell death which was so severe at a dose of 60 microM-min that contractility fell below control values. Below a threshold dose of 0.1 microM-min, acrolein had no effect on contractility. The role arachidonic acid metabolism in the enhancement of smooth muscle reactivity to carbachol was studied using indometacin to block the cyclo-oxygenase pathway and NDGA to block the lipoxygenase pathway. At a concentration of 10 microM of either indometacin or NDGA, the acrolein-induced enhancement in airway reactivity was completely inhibited. At lower concentrations, inhibition by these two chemicals was partially additive, suggesting that both the lipoxygenase and cyclo-oxygenase pathways play a role in the hyperreactive response.

Acrolein↗

PubMed1993

Effect of passive sensitization on the mechanical activity of human isolated bronchial smooth muscle induced by substance P, neurokinin A and VIP.

1. The effect of passive sensitization on the mechanical activity of human isolated bronchial smooth muscle induced by the following neuropeptides substance P (SP), neurokinin A (NKA) and vasoactive intestinal peptide (VIP) was studied both in the absence and in the presence of the neutral endopeptidase (NEP) inhibitor, phosphoramidon. 2. Cumulative concentration-response curves (CCRC) to these neuropeptides were constructed in human passively sensitized isolated bronchial rings and compared to those in paired controls. Passively sensitized human isolated bronchial rings were tissues incubated overnight in serum from asthmatic patients atopic to Dermatophagoides pteronyssinus and paired controls were tissues originating from the same lung specimens but incubated overnight in serum from healthy donors. 3. In the absence of phosphoramidon, passive sensitization significantly increased the amplitude of the contractile responses to SP and NKA including that to the maximal concentration given from 50 +/- 5% to 76 +/- 6% (n = 5, P < 0.05) and from 70 +/- 7% to 101 +/- 6% (n = 5, P < 0.05) of the maximal response to acetylcholine, respectively. Passive sensitization significantly shifted to the left the CCRC for both tachykinins as measured by the geometric means dose-ratios which were 8.5 (95% confidence limits (CL): 3.1-13.9) and 7.3 (95% CL: 4.2-10.3) for SP and NKA, respectively. 4. In the presence of phosphoramidon (10 microM), passive sensitization still increased significantly the amplitude of the contractile responses to SP and NKA including that to the maximal concentration given from 74 +/- 4% to 115 +/- 7% (n = 5, P<0.05) and from 104 +/- 9% to 146 +/- 16% (n = 5, P<0.05)of the maximal response to acetylcholine, respectively. Passive sensitization still significantly shifted to the left the CCRC for both tachykinins as measured by the dose-ratios which were 9.0 (95% CL:4.3-13.6) and 5.4 (95% CL: 2.9-7.9) for SP and NKA, respectively.5. The relaxant response to the maximal concentration of VIP given in tissues precontracted with histamine (0.5 mM) was significantly reduced by passive sensitization from 41 +/- 4% to 25 +/- 3% (n = 5,P <0.05) of the amplitude of the precontraction in the absence of phosphoramidon and from 72 +/- 1%to 49 +/- 4% (n = 5, P<0.05) in the presence of phosphoramidon (10 microM). Passive sensitization significantly shifted to the right the CCRC for VIP as measured by the dose-ratios which were 10.4(95% CL: 6.6-14.1) and 6.4 (95% CL: 3.0-9.8) in the absence and in the presence of phosphoramidon,respectively.6. We conclude that passive sensitization enhances the mechanical response to neuropeptides which contract human isolated bronchial smooth muscle and reduces that to a neuropeptide which relaxes it.The mechanism of passive sensitization-induced changes in the mechanical activity appears to be independent of a decrease in NEP activity since these changes persist in the presence of the NEP inhibitor, phosphoramidon.

Acetylcholine↗