Effects of tidal volume stretch on airway constriction in vivo.

Tidal stresses are thought to be involved in maintaining airway patency in vivo. The present study examined the effects of normal stresses exerted by the lung parenchyma during tidal ventilation on recovery from agonist-induced airway constriction. In seven anesthetized dogs, one lung was selectively ventilated with a Univent endotracheal tube (Vitaid, Lewiston, NY). Airway tone was increased either transiently (intravenous bolus) or continuously (intravenous infusion) with methacholine (MCh). During one-lung ventilation, changes in the airway size of both lungs were measured for up to 40 min during recovery from constriction by using high-resolution computed tomography. After recovery to baseline, the alternate lung was ventilated, and the protocol was repeated. The absence of tidal stresses led to an attenuated recovery from either transient or steady-state airway constriction. The effectiveness or lack thereof of normal tidal stress in stabilizing airway size may be one factor that contributes to the lack of reversal with tidal breathing and deep inspiration seen in asthmatic subjects.     

Differences between inhaled and intravenous bronchial challenge to detect O(3)-induced hyperresponsiveness.

Ozone (O(3))-induced airway hyperresponsiveness in laboratory animals is usually demonstrated through dose-response curves with inhaled or intravenous bronchoconstrictor agonists. However, comparability of these two routes has not been well documented. Thus guinea pig airway responsiveness to ACh and histamine was evaluated 16-18 h after O(3) (3 parts/million, 1 h) or air exposure by two plethysmographic methods (spontaneously breathing and mechanically ventilated) and by two administration routes (inhalatory or intravenous). We found that O(3) caused airway hyperresponsiveness to intravenous, but not to inhaled, agonists, independent of the plethysmographic method used. Suitability of the inhalatory route to detect airway hyperresponsiveness was corroborated with inhaled ACh after an antigen challenge or extending O(3) exposure to 3 h. Acetylcholinesterase activity was not modified after O(3) exposure in lung homogenates and blood samples. Thus inhaled agonists were less effective to reveal the airway hyperresponsiveness after an acute O(3) exposure than intravenous ones, at least for the 1-h exposure to 3 parts/million, and this difference seems not to be related to an O(3)-induced inhibition of the acetylcholinesterase activity.     

Feasibility of the laryngeal tube airway for artificial ventilation in pigs and comparison with the laryngeal mask airway

Airway management in anesthetized pigs is known to be technically demanding, and the 'gold standard' technique of endotracheal intubation is particularly difficult to master. The authors investigated the feasibility of the laryngeal tube as an alternative technique for airway management in German Landrace pigs (n = 5). They compared this method with the laryngeal mask, which is considered to be an effective yet relatively straightforward tool for porcine airway management. One after the other, investigators attempted to establish an airway in each anesthetized, artificially ventilated pig using each device. The laryngeal tube was too short to intubate the largest pig (weighing 45 kg), and it took investigators slightly longer to insert this device compared with the laryngeal mask. With the laryngeal mask, there were several incidents of gastric insufflation. Despite these complications, all investigators were able to establish a secure airway and maintain oxygenation with the laryngeal tube, and all subjectively rated both devices as easy to use.     

Occupational exposure to isoflurane during anaesthesia induction with standard and scavenging double masks in dogs, pigs and ponies

Induction of anaesthesia using a face mask may cause workplace pollution with anaesthetics. The aim of this study was to compare the effect of the use of a standard versus a scavenging double face mask on isoflurane pollution during induction of anaesthesia in experimental animals: six dogs, 12 pigs and five ponies. Pigs were anaesthetized only once using either mask type randomly (n = 6). Dogs and ponies were anaesthetized twice, using different mask types for each occasion in a random order with at least 14 days between experiments. The masks were attached to a Bain breathing system (dogs and pigs) or to a circle system (ponies) using a fresh gas flow of 300 or 50 mL/kg/min, respectively, with 5% vaporizer dial setting. Isoflurane concentrations were measured in the anaesthetist's breathing zone using an infrared photoacoustic spectrometer. The peak isoflurane concentrations (pollution) during baseline and induction periods were compared with Wilcoxon test in all species, and values between the mask types were compared with either Wilcoxon (ponies and dogs) or Mann-Whitney tests (pigs) (P < 0.05). Pollution was higher during induction when compared with baseline regardless of the mask type used but it was only statistically significant in dogs and pigs. Pollution was lower during induction with double versus single masks but it was only significant in pigs. Despite the lack of statistical significance, large and consistent differences were noted in all species, hence using scavenging masks is recommended to reduce isoflurane workplace pollution.     

Leukotriene B4 potentiates airway muscle responsiveness in vivo and in vitro

We studied the effects of leukotriene B4 (LTB4) on guinea pig airway muscle responsiveness in vivo and in vitro. Responsiveness in vivo was assessed by measuring specific airway resistance (SRaw) upon intravenous acetylcholine infusion in 5 unanesthetized, spontaneously breathing guinea pigs. We found that aerosolized LTB4, in a concentration that itself had no effect on baseline SRaw, caused a substantial increase in bronchial reactivity to i.v. ACh within 8 min of its administration. Responsiveness in vitro was assessed by measuring isometric contraction of the guinea pig trachealis upon stimulation by either chemical or electrical field stimuli. These studies in vitro showed that a concentration of LTB4 that itself did not cause contraction, potentiated airway muscle contraction to ACh and KCl, but not to norepinephrine. This effect of LTB4 was substantially reduced by nifedipine. Our data suggests that amounts of LTB4 that are themselves non-contractile in vivo or in vitro, may directly potentiate the responsiveness of airway smooth muscle to other bronchoconstrictors.     

U-60,257 inhibits O3-induced bronchial hyperreactivity in the guinea pig

We studied the effects on ozone-induced airway hyperreactivity of U-60,257, a pyrroloprostacyclin shown to inhibit leukotriene C/D biosynthesis in vitro. A group of 5 guinea pigs were pretreated with U-60,257 (5 mg/kg IV), and studied before and 30 min after a 15 min exposure to 3.0 ppm ozone. These animals were compared to a similarly exposed group that was untreated (n = 10). Reactivity was determined by measuring specific airway resistance (SRaw) upon intravenous acetylcholine infusion in unanesthetized, spontaneously breathing animals. Prior to ozone exposure, we found that U-60,257 treatment did not affect either SRaw or muscarinic reactivity. After exposure to 3.0 ppm, all untreated guinea pigs showed substantial muscarinic hyperreactivity. In contrast, no significant change in SRaw or muscarinic reactivity occurred after ozone in any animal pretreated with U-60,257. We conclude that ozone-induced bronchial hyperreactivity in the guinea pig rapidly develops after a brief, high level exposure. This effect may be mediated, in part, by leukotrienes generated upon ozone exposure.     

A new airway device for small laboratory animals

There is a need for a device for improved management of the airway of small laboratory animals during general anaesthesia. This report introduces such a device, referred to here as the airway device (AD). The AD has some similarity to the laryngeal mask airway (LMA) developed for human patients, but the mask portion of the device is specifically designed for small laboratory animals. In addition, the device has an oesophageal extension and unlike the LMA does not have a cuff associated with the mask. This report also shares experience of tests of one prototype AD with six New Zealand white rabbits. The AD was used for administering isoflurane and its effectiveness was evaluated during conditions of spontaneous and controlled intermittent positive pressure ventilation. The results provide encouragement for further development of the AD for airway management of small laboratory animals.     

A long-term porcine model for measurement of gastrointestinal motility

Animal models have become an essential tool in the investigations of gut motility under experimental conditions. To determine the influence of various anaesthetic drugs on the motility pattern of the gastroduodenal tract, a new long-term model has had to be developed for allowing measurements in conscious and unrestrained as well as in sedated and analgosedated pigs. Since mechanical ventilation influences gut motility, it was necessary that this animal model enabled the investigation of the effect of drugs causing sedation and analgosedation during spontaneous breathing. Seven male, castrated pigs, German landrace, 32-40 kg bodyweight (BW) were investigated in this study. After habituation of the pigs to local housing conditions over 5 days, the animals were trained over 4 days to prepare for experimental situations and investigators. Pigs were inserted with a central venous catheter and with percutaneous enterogastrostomy (PEG) under general anaesthesia. Intestinal motility was measured by intraluminal impedancometry. The catheter was introduced over the PEG into the stomach and positioned into the duodenum by duodenoscopy. Measurements were done in conscious, unrestrained pigs and with sedated, and analgosedated animals on subsequent days. The habituation and training of the pigs to the investigators and for the laboratory conditions took between 7 and 9 days. The initial anaesthesia protocol for the instrumentation using remifentanil/propofol led to pyloric spasm and was thus unsuitable for duodenal intubation with an endoscope. In contrast, a combination of ketamine/propofol enabled this procedure. It was practicable to measure gut motility in conscious, unrestrained pigs. Spontaneous breathing was sufficient under propofol sedation and analgosedation using fentanyl-propofol. Systematically local application of polividon iodine in the area of the subcutaneous catheters avoided the necessity of using systemic prophylactic antibiotics. In conclusion, the habituation and training for 9 days enabled the measurement of gut motility by intraluminal impedancometry in conscious pigs. The insertion of the catheter was done during general anaesthesia using a combination of propofol and ketamine. For the future determination of gut motility performed under general anaesthesia, each sedation and analgosedation concept has to be evaluated to see whether it allows spontaneous breathing or whether mechanical ventilation is necessary.     

U-60, 257 inhibits O3-induced bronchial hyperreactivity in the guinea pig

We studied the effects on ozone-induced airway hyperreactivity of U-60, 257, a pyrroloprostacyclin shown to inhibit leukotriene C/D biosynthesis in vitro. A group of 5 guinea pigs were pretreated with U-60, 257 (5 mg/kg IV), and studied before and 30 min after a 15 min exposure to 3.0 ppm ozone. These animals were compared to a similarly exposed group that was untreated (n=10). Reactivity was determined by measuring specific airway resistance (SRaw) upon intravenous acetylcholine infusion in unanesthetized, spontaneously breathing animals. Prior to ozone exposure, we found that U-60, 257 treatment did not affect either SRaw or muscarinic reactivity. After exposure to 3.0 ppm, all untreated guinea pigs showed substantial muscarinic hyperreactivity. In contrast, no significant change in SRaw or muscarinic reactivity occurred after ozone in any animal pretreated with U-60, 257. We conclude that ozone-induced bronchial hyperreactivity in the guinea pig rapidly develops after a brief, high level exposure. This effect may be mediated, in part, by leukotrienes generated upon ozone exposure.     

Changes in minimal alveolar concentration of isoflurane following treatment with medetomidine and tiletamine/zolazepam, epidural morphine or systemic buprenorphine in pigs

The aim of this study was to determine the changes in minimal alveolar concentration (MAC) of isoflurane after treatment with medetomidine and tiletamine/zolazepam (MTZ), epidural morphine or systemic buprenorphine in 11 healthy crossbred pigs. The first part of this study was to measure the baseline values in pigs induced with isoflurane (5%) by face mask and maintained with isoflurane in air and oxygen for 2 h (ISO). Baseline isoflurane MAC was determined using mechanical stimulation. Thereafter, each pig was randomly chosen for a crossover test in which the same animal received three different treatments with at least one week in between treatments. The three treatments were as follows: induction of anaesthesia with medetomidine (0.05 mg kg(-1)) and tiletamine/zolazepam (2.5 mg kg(-1) each) given intramuscularly (MTZ); MTZ followed by epidural morphine (0.1 mg kg(-1); MTZ/M); and MTZ followed by intramuscular buprenorphine (0.1 mg kg(-1); MTZ/B). All pigs were maintained with isoflurane in oxygen and air for 2 h and their lungs were mechanically ventilated. The end-tidal isoflurane concentration, respiratory rate, inspiratory and expiratory O2 and CO2 concentrations, heart rate (HR) and arterial blood pressure were recorded every 10 min. Arterial blood gases were analysed every 20 min. Among the treatment groups, differences in isoflurane MAC were tested using GLM and Tukey's method for further comparison; P < 0.05 was adopted as significant. Isoflurane MAC was 1.9 +/- 0.3%. MTZ reduced isoflurane MAC to 0.6 +/- 0.1%. Additional morphine or buprenorphine reduced the MTZ isoflurane MAC further to 0.4 +/- 0.2 and 0.3 +/- 0.1%, respectively. During MTZ, MTZ/M and MTZ/B mean arterial blood pressure was higher and the alveolar-arterial oxygen tension difference was lower compared with ISO. In conclusion, induction of anaesthesia with MTZ reduced the isoflurane MAC in pigs by 68%. Additional epidural morphine or systemic buprenorphine decreased MTZ isoflurane MAC by 33 and 50%, respectively.     

Endothelin-induced vascular and bronchial effects in pig airways: role in acute allergic responses.

The effects of endothelin (ET) agonists on airway mechanics and bronchial blood flow were studied as well as the effects of mixed ET-receptor antagonist bosentan on allergen-induced airway reactions in the pig. ET agonists [ET-1, ET-3, and the ET(B) receptor-selective agonist Sarafotoxin 6c (Sf6c)] were given as intravenous injections (0.4-200 pmol/kg) to eight anesthetized pigs. Bosentan (10 mg/kg iv) was then administered, and the injections were repeated. Only Sf6c caused a significant increase in airway resistance, and this response was blocked by bosentan. Sf6c and ET-1 (200 and 400 pmol/kg, respectively) were also given as aerosols to five pigs. Sf6c, but not ET-1, caused bronchoconstriction via this route. All agonists (intravenous) caused increases in bronchial vascular conductance, an effect that was blocked by an NO-synthase inhibitor (N(G)-nitro-L-arginine) but unaffected by a cyxlooxygenase inhibitor (diclofenac). Fourteen pigs were sensitized with ascaris suum antigen. Under anesthesia, eight pigs were pretreated with bosentan, and six pigs were controls. They were all challenged with allergen aerosol resulting in acute bronchoconstriction and elevation of ET-1 in bronchoalveolar lavage fluid. Bosentan did not affect the maximal acute airway obstruction but markedly increased baseline bronchial vascular conductance, suggesting a basal vascular tone regulated by ETs. In conclusion, ETs induce bronchoconstriction primarily via the ET(B) receptor in the pig. However, ETs are probably not involved in the allergen-induced acute bronchoconstriction in this model.     

Leukotriene B4 potentiates airway muscle responsiveness and

We studied the effects of leukotriene B₄ (LTB₄) on guinea pig airway muscle responsiveness and . Responsiveness in vivo was assessed by measuring specific airway resistance (SRaw) upon intravenous acetylcholine infusion in 5 unanesthetized, spontaneously breathing guinea pigs. We found that aerosolized LTB₄, in a concentration that itself had no effect on baseline SRaw, caused a substantial increase in bronchial reactivity to i.v. ACh within 8 min of its administration. Responsiveness was assessed by measuring isometric contraction of the guinea pig trachealis upon stimulation by either chemical or electrical field stimuli. These studies showed that a concentration of LTB₄ that itself did not cause contraction, potentiated airway muscle contraction to ACh and KCl, but not to norepinephrine. This effect of LTB₄ was substantially reduced by nifedinpine. Our data suggests that amounts of LTB₄ that are themselves non-contractile or in , may directly potentiate the responsiveness of airway smooth muscle to other bronchoconstrictors.     

Lack of adrenomedullin on antigen-induced bronchoconstriction in guinea pigs in vivo

Antigen challenge can provoke acute bronchoconstriction, recognized as immediate asthmatic response (IAR), but the evolving events in this reaction are not well defined. Recently, a novel peptide, designated adrenomedullin, was isolated from human pheochromocytoma, and has been shown to have potent systemic and pulmonary vasodilator activity.The purpose of this study was to elucidate the influence of adrenomedullin in the development of IAR. Passively sensitized guinea pigs were anesthetized and treated with diphenhydramine hydrochloride, and then artificially ventilated. Ovalbumin was inhaled after an intravenous administration of adrenomedullin. Other studies were performed in naive guinea pigs to investigate the airway responses to inhaled methacholine or histamine after an intravenous administration of adrenomedullin. Antigen challenge caused bronchoconstriction in sensitized guinea pigs. Adrenomedullin did not inhibit the antigen-induced bronchoconstriction in sensitized guinea pigs or the dose-dependent responses to inhaled methacholine or histamine in naive animals in spite of its vasodilating effect. We conclude that an intravenous administration of adrenomedullin does not influence antigen-induced bronchoconstriction or bronchial responsiveness to inhaled methacholine or histamine in vivo.     

A comparison of the radiation response of the epidermis in two strains of pig

The response of the epidermis was compared in two strains of pig, the English Large White and the G?ttinger Miniature, after irradiation with 90Sr beta rays. The effects of two types of anesthesia were also tested in pigs of each strain, a volatile gas mixture of approximately 70% oxygen, approximately 30% nitrous oxide, and 2% halothane, and an intravenously administered narcotic azaperon/etimodat with the animals breathing air. Strain- and anesthetic-related changes were compared on the basis of dose-effect curves for the incidence of moist desquamation from which ED50 values (+/- SE) were determined, i.e., the dose required to produce this effect in 50% of the fields irradiated. For English Large White pigs anesthetized with the volatile gas mixture, an ED50 of 27.32 +/- 0.52 Gy was obtained for moist desquamation. Irradiation with the azaperon/etomidat anesthesia in this strain of pig produced a significantly higher ED50 of 33.36 +/- 0.76 Gy (P less than 0.001). This appeared to be related to the fact that the animals were breathing air, i.e., a lower oxygen concentration (approximately 21%), at the time of irradiation. For the G?ttinger Miniature pig the ED50 values for moist desquamation were 38.93 +/- 3.12 Gy and 43.36 +/- 1.34 Gy while using the gaseous anesthetic mixture and the azaperon/etomidat anesthesia with the animals breathing air, respectively. These ED50 values are 10-11 Gy higher than those obtained for the English Large White pig under identical conditions of anesthesia, which resulted in a strain difference ratio of approximately 1.35. Radiation under the volatile gas mixture anesthesia resulted in a uniform irradiation response over the skin of the flank in both strains of pig. Radiation under azaperon/etomidat anesthesia resulted in a nonuniform skin response over the flank. The ED50 for moist desquamation was significantly higher in dorsal sites on the flank compared with the ventral area of English Large White pigs; a similar trend was seen in G?ttinger Miniature pigs. This difference in the radiosensitivity over the flank skin while the animals are under azaperon/etomidat anesthesia at the time of irradiation was associated with the animals breathing air and is in agreement with findings published previously for animals under halothane anesthesia and breathing air.     

Middle-latency auditory evoked potentials during induction of thiopentone anaesthesia in pigs.

A method is described for measuring middle-latency auditory evoked potentials (MLAEP) in consciously awake, non-sedated pigs during the induction of thiopentone anaesthesia (0.6 ml/kg, 2.5% thiopentone solution). It was done by using autoregressive modelling with an exogenous input (ARX). The ability to perceive pain during the induction was compared with (1) the changes in latencies and amplitudes of the MLAEP, (2) the change in a depth of anaesthesia index based on the ARX-model and (3) the change in the 95% spectral edge frequency. The pre-induction MLAEP was easily recordable and looked much like the one in man, dogs and rats. The temporal resolution in the ARX method was sufficiently high to describe the fast changes occurring during induction of thiopentone anaesthesia. As previously reported from studies in man, dogs and rats, induction of thiopentone anaesthesia resulted in significantly increased latencies and decreased amplitudes of the MLAEP trace as well as in a significantly reduced depth of anaesthesia index and spectral edge frequency. None of the changes, however, related well to the ability to react to a painful stimulus. Whether an ARX-based depth of anaesthesia index designed especially for pigs might be better than the present index (designed for man) for assessing depth of anaesthesia must await the results of further studies.     

In vivo airway eosinophil accumulation does not enhance antigen- or propranolol-induced bronchoconstriction in guinea pigs

BACKGROUND: Chronic airway eosinophil accumulation is characteristic of asthma. However, it remains unclear whether airway eosinophils enhance or reduce release of chemical mediators and/or action of the released mediators in the airways in vivo, because previous investigators have indicated that eosinophil-derived factors such as histaminase and arylsulfatase may alter the allergic reaction by metabolizing chemical mediators. Recently, we have developed a guinea pig model of propranolol-induced bronchoconstriction (PIB), which is mediated by lipid mediators such as thromboxane A2 (TxA2), cysteinyl leukotrienes (cLTs) and platelet activation factor (PAF). This study was conducted to explain the influence of airway eosinophil accumulation on antigen-induced bronchoconstriction and the following PIB, both of which are mediated by lipid mediators. METHODS: Guinea pigs were transnasally treated with 75 microg/kg of polymyxin-B or vehicle twice a week for a total of 3 weeks. Guinea pigs were anesthetized and treated with diphenhydramine hydrochloride, and then artificially ventilated 24 h after the last administration of polymyxin-B or vehicle followed by passive sensitization. Propranolol at a concentration of 10 mg/ml was inhaled 20 min after an aerosolized antigen challenge. RESULTS: The proportion of eosinophils in bronchoalveolar lavage fluid obtained 15 min after the propranolol inhalation was significantly increased in guinea pigs treated with polymyxin-B compared with the vehicle. The polymyxin-B treatment did not affect antigen-induced bronchoconstriction or the following PIB. CONCLUSIONS: We conclude that eosinophils accumulated in the airways by polymyxin-B does not affect release of chemical mediators induced by antigen or propranolol inhalation, or action of released mediators in vivo.     

PGF2 alpha and breathing pattern in newborn pigs

The effect of PGF2 alpha has been evaluated in 11 unanaesthetized unrestrained piglets and in 3 anaesthetized piglets (2-3 days old) using a barometric-plethysmographic technique. PGF2 alpha (mg 0.25/pig) was administered as aerosol for 5 min. In 3 of the unanaesthetized newborn pigs the effect of PGF2 alpha aerosol has been evaluated after indomethacin (mg 1/Kg i.v.). The vagal dependent activity of the prostaglandin was also evaluated after atropine (mg 0.08/Kg i.m.). Our results show that PGF2 alpha in newborn pigs causes hypoventilation due to a decrease in respiratory rate and to a lengthening in TE. The changes in TE are due to an increase in the incidence and duration of apneic events characterizing the respiratory activity at birth. After indomethacin PGF2 alpha does not change the breathing pattern. Atropine only partially reduces the effects of PGF2 alpha while, after anaesthesia, prostaglandin does not change the breathing pattern. Consequently our results show that PGF2 alpha in newborn animals similar to other prostaglandins acts as a depressant of respiratory activity.     

Prevention of abnormal pulmonary mechanics in the postmortem guinea pig lung

Severe postmortem bronchoconstriction has been shown previously in guinea pig lungs and linked to pulmonary blood loss during exsanguination (Lai et al., J. Appl. Physiol. 56: 308-314, 1984). To reexamine this phenomenon we measured postmortem airway function in anesthetized open-chest guinea pigs after sudden circulatory arrest. Animals were divided into 4 groups of 10 and ventilated for 15 min postmortem with different gases: 1) room air, 2) conditioned air, 3) dry 5% CO2-21% O2-74% N2, and 4) conditioned 5% CO2-21% O2-74% N2. In room air-ventilated lungs there was a 50% decrease in dynamic compliance (Cdyn) by 15 min and marked gas trapping compared with control lungs. Conditioning the room air did not attenuate these changes, but when 5% CO2 was added to the conditioned postmortem inspirate, gas trapping was eliminated and the fall in Cdyn was almost abolished. Ventilation with a dry 5% CO2 gas mixture at room temperature resulted in a 31% fall in Cdyn at 15 min but no gas trapping. We conclude that marked abnormalities of airway function occur postmortem in room air-ventilated guinea pig lungs in the absence of pulmonary blood loss. The changes are mainly due to airway hypocarbia, a known cause of bronchoconstriction, but a reduction in Cdyn can also occur if there is marked airway cooling and drying. Acute postmortem airway dysfunction can be prevented in the guinea pig by maintaining normal airway gas composition.     

Inhaled nitric oxide reverses PAF-dependent bronchoconstriction in the pig

In six anesthetized, paralyzed, mechanically ventilated pigs we evaluated the respiratory effects of inhaled nitric oxide (NO) (80 ppm in O₂) under control conditions and after platelet-activating factor (PAF) administration (50 ng/kg, i.v.). PAF was also administered to the same pigs after pretreatment with indomethacin (3 mg/kg, i.v.). The mechanical properties of the respiratory system were evaluated by the rapid airway occlusion technique. With this technique the overall respiratory resistances, the airway resistances, and the additional resistances of respiratory system and lung can be evaluated. The results show that NO inhaled by the pig at 80 ppm for 6 min under control conditions reduced static and dynamic elastances of the respiratory system and lung and pulmonary arterial pressure, without modifying bronchomotor tone. Therefore, NO reduced the PAF-dependent changes in resistances and in static and dynamic elastances of the respiratory system and lung. The modest change in elastances caused by PAF in pigs pretreated with indomethacin was reduced by NO inhalation, which also has a mild bronchodilatory effect. The changes in elastances appear to be correlated with the pulmonary vasodilator activity of inhaled NO.     

Aerosolized neutral endopeptidase reverses ozone-induced airway hyperreactivity to substance P.

We investigated the effects of ozone exposure (3.0 ppm, 2 h) on airway neutral endopeptidase (NEP) activity and bronchial reactivity to substance P in guinea pigs. Reactivity after ozone or air exposure was determined by measuring specific airway resistance in intact unanesthetized spontaneously breathing animals in response to increasing doses of intravenous substance P boluses. The effective dose of substance P (in micrograms) that produced a doubling of baseline specific airway resistance (ED200SP) was determined by interpolation of cumulative substance P dose-response curves. NEP activity was measured in tracheal homogenates made from each animal of other groups exposed to either ozone or room air. By reverse-phase high-pressure liquid chromatography, this activity was characterized by the phosphoramidon-inhibitable cleavage of alanine-p-nitroaniline from succinyl-(Ala)3-p-nitroaniline in the presence of 100 microM amastatin. Mean values of the changes in log ED200SP were 0.27 +/- 0.07 (SE) for the ozone-exposed group and 0.08 +/- 0.04 for the air-exposed group. We found that phosphoramidon significantly increased substance P reactivity in the air-exposed animals (P less than 0.01), but it had no effect in the ozone-exposed group. This finding was associated with a significant reduction in tracheal homogenate NEP activity of ozone-exposed animals compared with controls: mean values were 18.1 +/- 1.9 nmol.min-1.mg protein-1 for the ozone-exposed group and 25.1 +/- 2.4 nmol.min-1.mg protein-1 for air-exposed animals (P less than 0.05). Inhalation of an aerosolized NEP preparation, partially purified from guinea pig kidney, reversed the substance P hyperreactivity produced by ozone exposure.(ABSTRACT TRUNCATED AT 250 WORDS)