Acute effects of cigarette smoke inhalation on peripheral airways in dogs

We studied the acute effects of the inhalation of cigarette smoke on the central and peripheral airways of 35 open-chested and tracheotomized dogs by the direct measurement of central (Rc) and peripheral (Rp) airway resistances. Rc was calculated by dividing the pressure difference between a tracheal catheter and a retrograde catheter by mouth flow, and Rp was obtained by dividing the pressure difference between the retrograde catheter and a pleural capsule by mouth flow. The pleural capsule was attached to the pleural surface for alveolar pressure measurement. Rc and Rp were measured by the 2-Hz forced oscillation method. With lung inhalation of the smoke of two-thirds of one cigarette in vagi intact dogs, Rp increased to 239% of the control value and Rc increased to 112%. After bilateral vagotomy, Rp increased to 143% and Rc increased to 104%. Propranolol did not influence the results. Hexamethonium and atropine both blocked these responses when vagi were intact. When the upper trachea, larynx, and nasopharynx, which were completely blocked by vagotomy, were exposed to the smoke of two-thirds of a cigarette, Rp increased to 155% and Rc increased to 144%. We thus conclude that cigarette smoke causes a major increase in Rp, mainly via the vagal reflex and partially via the stimulation of parasympathetic ganglia (probably nicotine), and a minor increase in Rc via vagal reflex.     

Sympathetic and parasympathetic nervous control of airway resistance in dog lungs

We studied autonomic nervous control of central (Rc), peripheral (Rp), and extremely peripheral (Rep) airway resistances using a combination of a retrograde catheter method and a pleural capsule method. Airflow through the pleural capsule enabled us to measure Rep, which mainly reflected the resistance of local bronchioles less than 0.6 mm in diameter. Rp of the airways less than about 2 mm in diameter was not negligibly small at any lung volume (VL). With vagi intact, Rc increased at high as well as low VL, whereas Rp and Rep increased sharply as VL decreased. Vagal stimulation increased Rp more markedly than Rc, and Rep least of all. Propranolol augmented total airway resistance (Rtot) two to four times as much as vagal stimulation, mainly because of increased Rp. Stimulation of stellate ganglia inhibited up to half the increase of Rtot elicited by vagal stimulation; most of the inhibition occurred in Rp, but little in Rc and Rep. Our data suggest that both sympathetic and parasympathetic control is more extensive for Rp than for Rc or Rep.     

Effects of aerosol histamine and carbachol on central and peripheral airflow resistance in sheep

Sixteen anesthetized artificially ventilated open-chest sheep were prepared with retrograde catheters to allow for measurement of dynamic compliance of the lungs (Cdyn), total airflow resistance of the lungs (RL), and central (Rc) and peripheral (Rp) airflow resistance. Twelve sheep received aerosol histamine and 12 sheep received aerosol carbachol. Eight sheep received and responded to both aerosol histamine and aerosol carbachol. Three sheep received both aerosol histamine and aerosol carbachol but failed to respond to both agents. Under base-line conditions, for the 16 sheep, 69% of total RL was located in the peripheral component, Rp, and 31% in the central component, Rc. Aerosol histamine caused only peripheral small airway changes while aerosol carbachol predominantly effected the central large airways. When aerosol histamine responsiveness, defined using Cdyn or Rp, was compared to aerosol carbachol responsiveness using Rc, a correlation was demonstrable (r = 0.84, n = 8, P less than 0.05). It is possible in sheep to cause relatively pure peripheral small airway and relatively pure central large airway changes by using different bronchoconstrictor agents. Aerosol histamine and aerosol carbachol responsiveness correlated with each other in these artificially ventilated anesthetized sheep.     

Effects of hemodynamic edema formation on peripheral vs. central airway mechanics

The mechanisms governing increased central (Rc) and peripheral airway resistance (Rp) during hemodynamic edema formation were studied in anesthetized dogs. Rc and Rp were measured by forced oscillation at 1 Hz by use of a retrograde catheter to partition resistance and a pleural capsule to detect alveolar pressure. After elevation of left atrial pressure to 30 cmH2O by inflation of the left atrial balloon, Rc gradually increased an average of 60% above control in approximately 100 min. Vagotomy had a small influence on the change. On the other hand, Rp with vagus nerves intact increased triphasically: first, it increased transiently by 160% above the control value within 15-20 min before returning to near base line. It then increased gradually for approximately 40 min and finally rose sharply up to five times the control value after approximately 100 min. With vagi cut, the initial phase disappeared, but the second gradual and final rapid phases were not affected. Several sequential mechanisms of increased Rp can be proposed: 1) transient bronchoconstriction mediated by vagal reflex; 2) gradual formation of peribronchial edema; and 3) a sharp increase in airway fluid and formation of bronchial froth. In addition, narrowing of the airways by vascular engorgement may have contributed to the increase of Rp throughout all stages.     

Vagal control of central and peripheral pulmonary resistance in developing piglets

To study the postnatal maturation of vagal control of airway muscle tone, we determined the effects of vagotomy and supramaximal vagal stimulation on the resistance of the respiratory system in eight newborn and seven 6-wk-old piglets. Because the lung periphery has distinctive responses to cholinergic agonists and a lower density of vagal fibers and cholinergic receptors than the central airways, we partitioned the respiratory resistance of the piglets between central airways (Rc) and peripheral airways and lung tissue (Rp) with bronchial catheters inserted in a retrograde manner. The piglets were anesthetized with alpha-chloralose and ventilated with positive airway pressure. Vagotomy did not change Rc or Rp in either the newborn or the 6-wk-old piglets. Vagal stimulation, on the other hand, increased both Rc (median increase 53% in the newborn and 72% in the 6-wk-old piglets) and Rp (54 and 42%, respectively). At all states of vagal tone, Rp increased as the lungs were inflated, suggesting a large contribution of tissue viscoelasticity to this resistance. Our results demonstrate that vagal bronchomotor tone is absent during mechanical ventilation with positive pressure in the developing piglet. However, vagal innervation of both central airways and tissue contractile elements is functionally competent at the time of birth in this species.     

Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure.

To partition the central and peripheral airway resistance in awake humans, a catheter-tipped micromanometer sensing lateral pressure of the airway was wedged into the right lower lobe of a 3-mm-ID bronchus in 5 normal subjects, 7 patients with chronic bronchitis, 8 patients with emphysema, and 20 patients with bronchial asthma. We simultaneously measured mouth flow, transpulmonary pressure, and intra-airway lateral pressure during quiet tidal breathing. Total pulmonary resistance (RL) was calculated from transpulmonary pressure and mouth flow and central airway resistance (Rc) from intra-airway lateral pressure and mouth flow. Peripheral airway resistance (Rp) was obtained by the subtraction of Rc from RL. The technique permitted identification of the site of airway resistance changes. In normal subjects, RL was 3.2 +/- 0.2 (SE) cmH2O.l-1.s and the ratio of Rp to RL was 0.24 during inspiration. Patients with bronchial asthma without airflow obstruction showed values of Rc and Rp similar to those of normal subjects. Although Rc showed a tendency to increase, only Rp significantly increased in those patients with bronchial asthma with airflow obstruction and patients with chronic bronchitis and emphysema. The ratio of Rp to RL significantly increased in three groups of patients with airflow obstruction (P less than 0.01). These observations suggest that peripheral airways are the predominant site of airflow obstruction, irrespective of the different pathogenesis of chronic airflow obstruction.     

Partitioning of pulmonary resistance in calves

Nine right apical lobes of healthy Friesian calves and 10 right apical lobes of double-muscled calves of Belgian White and Blue (BWB) breed were suspended in an airtight box, inflated at a constant transpulmonary pressure (Ptp), and subjected to quasi-sinusoidal pressure changes (amplitude: 0.5 kPa) at a frequency of 30 cycles/min. Lobar resistance (RL) was partitioned at six different lung volumes into three components: central airway resistance (Rc), small airway resistance (Rp), and tissue resistance (Rt). Pressure in small airways (2-3 mm ID) was measured with a retrograde catheter. Alveolar pressure was sampled in capsules glued onto the punctured pleural surface. RL was minimal at values of Ptp comprised between 0.5 and 0.7 kPa and increased at higher and lower values of Ptp. At a Ptp of 0.5 kPa, Rc, Rp, and Rt represented 30, 15, and 55% of RL, respectively, in Friesian calves and 25, 25, and 50% in BWB calves. Rp increased markedly at low lung volumes. Rt was responsible for the increase of RL at high Ptp. Rc tended to decrease at high Ptp. The significantly higher values of Rp in BWB calves (P less than 0.05) might explain the sensitivity of this breed to severe bronchopneumonia.     

Relationship of central and peripheral airway resistance to lung volume in dogs

We could not reconcile reported relationships between lung resistance measurements and lung volume with bronchographic and anatomic studies showing that airway diameters change monotonically with lung volume and that small airways change diameter proportionately at least as much as large ones. Accordingly we measured central and peripheral airways resistances with a new technique. The relevant pressures were measured with a tracheal cannula, a wedged retrograde catheter, and two parenchymal needles in seven open-chested dogs while pleural pressure was oscillated at 1 Hz. In contrast to previous studies, the volume dependency of peripheral resistance was at least as great as that of central resistance with vagi intact, the volume dependencies of central and peripheral resistances were not abolished by vagotomy, and neither resistance increased systematically at high volumes. Volume dependency of central resistance resembled predictions for isotropic expansion of airways with vagi cut but increased with bronchomotor tone. These results fit generally with bronchographic data. Previous studies may have been affected by volume dependency due to "tissue resistance" and catheter phase lags.     

Atropine pretreatment enhances airway hyperreactivity in antigen-challenged guinea pigs through an eosinophil-dependent mechanism

Airway hyperreactivity in antigen-challenged animals is mediated by eosinophil major basic protein (MBP) that blocks inhibitory M(2) muscarinic receptors on parasympathetic nerves, increasing acetylcholine release onto M(3) muscarinic receptors on airway smooth muscle. Acutely, anticholinergics block hyperreactivity in antigen-challenged animals and reverse asthma exacerbations in the human, but are less effective in chronic asthma. We tested whether atropine, given before antigen challenge, affected hyperreactivity, M(2) receptor function, eosinophil accumulation, and activation. Sensitized guinea pigs received atropine (1 mg/kg ip) 1 h before challenge and 6 h later. Twenty-four hours after challenge, animals were anesthetized, vagotomized, paralyzed, and ventilated. Airway reactivity to electrical stimulation of the vagi and to intravenous acetylcholine was not altered by atropine pretreatment in nonsensitized animals, indicating that atropine was no longer blocking postjunctional muscarinic receptors. Antigen challenge induced airway hyperreactivity to vagal stimulation that was significantly potentiated by atropine pretreatment. Bronchoconstriction induced by acetylcholine was not changed by antigen challenge or by atropine pretreatment. M(2) receptor function was lost in challenged animals but protected by atropine pretreatment. Eosinophils in bronchoalveolar lavage and within airway tissues were significantly increased by challenge but significantly reduced by atropine pretreatment. However, extracellular MBP in challenged airways was significantly increased by atropine pretreatment, which may account for reduced eosinophils. Depleting eosinophils with antibody to IL-5 before challenge prevented hyperreactivity and significantly reduced MBP in airways of atropine-pretreated animals. Thus atropine pretreatment potentiated airway hyperreactivity by increasing eosinophil activation and degranulation. These data suggest that anticholinergics enhance eosinophil interactions with airway nerves.     

Intravenous versus inhaled atropine for inhibiting bronchoconstrictor responses in dogs

We studied whether the muscarinic antagonist, atropine, given intravenously or by inhalation, inhibits the bronchoconstrictor responses to inhaled acetylcholine and to acetylcholine released by electrical stimulation of the vagus nerves to the same degree. We assessed bronchoconstrictor responses in anesthetized dogs by determining the increase in total pulmonary resistance before and after increasing doses of atropine and then constructing inhibition dose-response curves. Before atropine the responses to the two stimuli were equal in magnitude. After intravenous atropine (initial dose 0.12 micrograms/kg, total dose 16 micrograms/kg) both responses were progressively inhibited to a similar degree. By contrast, after inhaled atropine (initial dose 0.02 micrograms/kg, total dose 2.4 micrograms/kg) the response to acetylcholine inhalation was inhibited to a much greater degree than the response to vagal stimulation. Thus, in studies designed to inhibit bronchoconstriction due to an inhaled muscarinic agonist to the same degree as bronchoconstriction due to a vagal reflex, atropine might better be given intravenously than by inhalation.     

A comparison of the central and peripheral antimuscarinic effects of atropine and methylatropine injected systemically and into the cerebral ventricles

We compared the relative abilities of atropine sulfate and methylatropine, injected i.v. and into the cerebral ventricles (icv), to block pharmacological responses mediated through central and peripheral muscarinic receptors. The hypotensive response to i.v. injection of acetylcholine (peripheral muscarinic receptors) was inhibited 50% by i.v. injection of 14.3 nmol (5.5 micrograms)/kg methylatropine and 147.8n molar equivalents (50 micrograms)/kg atropine sulfate. A similar degree of inhibition followed icv injection of 49.4 nmol/kg methylatropine and 384.2 nmol equivalents/kg atropine sulfate, indicating significant leakage out of the ventricular space. The pressor response to icv injection of neostigmine (central muscarinic receptors) also was inhibited more effectively by icv methylatropine than by atropine sulfate. Methylatropine was not effective in blocking central muscarinic receptors when injected i.v.     

Prostaglandin F2 alpha increases responsiveness of pulmonary airways in dogs

We studied the effect of prostaglandin F2 alpha (PGF2 alpha) on the responsiveness of pulmonary airways in dogs. Airway responsiveness was assessed by determining the bronchoconstrictor response to increasing concentrations of acetylcholine aerosol delivered to the airways. In each of five dogs, we determined responsiveness during treatment with physiologic saline, histamine, or PGF2 alpha aerosols. The doses of histamine and PGF2 alpha were determined by establishing the largest dose of each which could be given to the dog without causing bronchoconstriction (subthreshold doses). We found that airway responsiveness was not significantly different during histamine treatment than after saline, however, responsiveness increased during treatment with PGF2 alpha. In addition, the hyperresponsiveness induced by PGF2 alpha was prevented by pretreatment with the ganglion blocking drug hexamethonium (5 mg/kg given intravenously). The results show that PGF2 alpha specifically increases the responsiveness of pulmonary airways in doses that do not cause bronchoconstriction, and suggest that the hyperresponsiveness involves a neural mechanism such as increased responsiveness of airway sensory nerves.     

Hypocapnia-induced constriction of the canine peripheral airways exhibits tachyphylaxis

Hypocapnia-induced constriction of peripheral airways may be important in regulating the distribution of ventilation in pathological conditions. We studied the response of the peripheral lung to hypocapnia in anesthetized, paralyzed, mechanically ventilated dogs using the wedged bronchoscope technique to measure resistance of the collateral system (Rcs). A 5-min hypocapnic challenge produced a 161 +/- 19% (mean +/- SE) increase in Rcs. The magnitude of this response was not diminished with repeated challenge or by atropine sulfate (1 mg base/kg iv), chlorpheniramine maleate (5 mg base/kg iv), or indomethacin (5 mg/kg iv). The response was reduced by 75% by isoproterenol (5 micrograms/kg iv) (P less than 0.01) and reduced by 80% by nifedipine (20 micrograms/kg iv) (P less than 0.05). During 30-min exposure to hypocapnia the maximum constrictor response occurred at 4-5 min, after which the response attenuated to approximately 50% of the maximum response (mean = 53%, range 34-69%). Further 30-min challenges with hypocapnia resulted in significantly decreased peak responses, the third response being 50% of the first (P less than 0.001). The inability of indomethacin or propranolol to affect the tachyphylaxis or attenuation of the response suggests that neither cyclooxygenase products nor beta-adrenergic activity was involved. Hence, hypocapnia caused a prompt and marked constrictor response in the peripheral lung not associated with cholinergic mechanisms or those involving histamine H1-receptors or prostaglandins. With prolonged exposure to hypocapnia there was gradual attentuation of the constrictor response with continued exposure and tachyphylaxis to repeated exposure both of which would tend to diminish any compensatory effect of hypocapnic airway constriction on the distribution of ventilation.     

Autonomic response characteristics of porcine airway smooth muscle in vivo

We studied the autonomic response characteristics of airways in 65 swine in vivo. Tracheal smooth muscle response was measured isometrically in situ; bronchial response was measured simultaneously as change in airway resistance and dynamic compliance. To determine the optimal resting length at which maximal tracheal contraction was obtained, length-tension studies were generated in four animals using maximal electrical stimulation of the vagus nerves determined from stimulus-response characteristics in eight other swine. Pharmacological studies were performed in 25 animals to determine the relative potency and intrinsic activity of agonists (acetylcholine greater than histamine much greater than norepinephrine) causing contraction of trachea and bronchial airways. In 13 swine, the effects of autonomic stimulation were studied by intravenous administration of dimethylphenylpiperazinium (DMPP) after muscarinic blockade with 1.5 mg/kg iv atropine. Tracheal contraction caused by topical application of 3.4 X 10(-4) mol histamine (13.4 +/- 1.54 g/cm) was 96 +/- 7.2% blocked by 25 micrograms/kg iv DMPP in adrenal-intact animals; minimal relaxation was demonstrated in adrenalectomized animals, indicating absence of substantial sympathetic innervation to porcine trachea. Nonadrenergic innervation was not demonstrated. After beta-adrenergic blockade, sympathetic stimulation caused alpha-adrenergic contraction in bronchial airways but not in trachea. These data define the unique response characteristics of the airways of swine and demonstrate their utility for acute experimental study of airway responses in vivo.     

Use of collateral airways to assess airway reactivity

We investigated the correlation between collateral airway reactivity and other indexes of lung reactivity in response to aerosol and intravenous (iv) challenges. In four anesthetized mongrel dogs, we measured the peripheral airway resistance (Rp) to gas flow out of a wedged lung segment in different lobes on multiple occasions. We obtained dose-response curves of peripheral airways challenged with iv histamine or aerosols through the bronchoscope. During the same iv bolus challenge, whole lung airway pressure (Paw) responses to histamine were also measured. On separate occasions, changes in lung resistance (RL) were measured after the whole lung was challenged with a histamine aerosol. Reactivity was assessed from the dose-response curves for Rp and RL as the PD50 (dose required to produce a 50% increase); for changes in Paw we calculated the PD15 (dose required to produce a 15% increase over baseline). Results for Rp showed considerably more variability among different lobes in a given animal with the aerosol challenge through the bronchoscope than with the iv challenge. With aerosol challenge there were no significant differences in the mean PD50 for Rp among any of the animals. However, with the iv challenge two of the dogs showed significant differences from the others in reactivity assessed with Rp (P less than 0.01). Moreover, the differences found in the peripheral airways with iv challenge reflected differences found in whole lung reactivity assessed with either iv challenge (Paw vs. Rp, r2 = 0.96) or whole lung aerosol challenge (RL vs. Rp, r2 = 0.84). We conclude that the measurement of the collateral resistance response to iv challenge may provide a sensitive method for assessing airway reactivity.     

Histamine-induced constriction of canine peripheral lung: an airway or tissue response?

We compared the histamine responsiveness of peripheral airways (less than 6.0 mm diam) and parenchymal tissues in eight anesthetized paralyzed open-chest mongrel dogs. We measured pressure in a peripheral bronchus by using an antegrade wedged catheter and pressure in the alveolar region subtended by the wedged bronchus by using an alveolar capsule. Sinusoidal volume oscillations at a frequency of 0.5 Hz were delivered by a linear motor pump into the segment through the wedged catheter. We calculated the resistance of the segment (Rseg) and partitioned Rseg into tissue viscance (i.e., proportional to the resistive pressure drop between the alveolus and the pleura) and peripheral airway resistance. Measurements were taken under baseline conditions and after delivery of increasing concentrations of aerosolized histamine (0.1 micrograms/ml to 100.0 mg/ml) into the segment. We found that the histamine responsiveness of the peripheral airways and lung tissues varied markedly within a given dog. In four of eight dogs the airways were more responsive to histamine, in three of eight the tissues were more responsive, and in one of eight the response was equivalent at the two sites. We conclude that in a given animal, there is marked heterogeneity in the histamine responsiveness of the peripheral airways and parenchymal tissues and that either may dominate responsiveness in the peripheral lung.     

Airway hyperresponsiveness to bronchoconstrictor challenge after wood smoke exposure in guinea pigs.

Prior airway exposure to wood smoke induces an increase in airway responsiveness to subsequent smoke inhalation in guinea pigs (Life Sci. 63: 1513, 1998; 66: 971, 2000). To further characterize this airway hyperreactivity, we investigated and compared the airway responsiveness to bronchoconstrictor challenge before and 30 min after sham air exposure or wood smoke exposure in anesthetized and artificially ventilated guinea pigs. Various doses of substance P (0.8-6.4 microg/kg), capsaicin (0.2-3.2 microg/kg), prostaglandin F2alpha (30-3000 microg/kg), histamine (1-8 microg/kg), or acetylcholine (5-20 microg/kg) were intravenously injected at 2-min intervals in successively increasing doses to obtain the dose required to provoke a 200% increase in baseline total lung resistance (ED200). Wood smoke exposure significantly lowered the ED200 of substance P, capsaicin, and prostaglandin F2alpha whereas sham air exposure failed to do so. Furthermore, wood smoke exposure did not significantly alter the ED200 of histamine or acetylcholine. Pretreatment with phosphoramidon (2 mg/kg), an inhibitor of the neutral endopeptidase (the major degradation enzyme of substance P), before smoke exposure did not significantly affect the smoke-induced reduction in ED200 of substance P. Sectioning both cervical vagi before smoke exposure did not significantly alter the smoke-induced reduction in ED200 of capsaicin or prostaglandin F2alpha. These results suggest that airway exposure to wood smoke acutely produces airway hyperresponsiveness to substance P, capsaicin, and prostaglandin F2alpha, but not to histamine or acetylcholine. Since the combination of phosphoramidon and wood smoke exposure did not result in an additive potentiation of smoke-induced airway hyperresponsiveness to substance P, it is suggested that an inhibition of the degradation enzyme of substance P may contribute to this increase in airway reactivity. Furthermore, vagally-mediated bronchoconstriction does not play a vital role in enhanced airway responsiveness to capsaicin or prostaglandin F2alpha.     

Exaggerated airway narrowing in mice treated with intratracheal cationic protein.

Airway hyperresponsiveness in mice with allergic airway inflammation can be attributed entirely to exaggerated closure of peripheral airways (Wagers S, Lundblad LK, Ekman M, Irvin CG, and Bates JHT. J Appl Physiol 96: 2019-2027, 2004). However, clinical asthma can be characterized by hyperresponsiveness of the central airways as well as the lung periphery. We, therefore, sought to establish a complementary model of hyperresponsiveness in the mouse due to excessive narrowing of the airways. We treated mice with a tracheal instillation of the cationic protein poly-l-lysine (PLL), hypothesizing that this would reduce the barrier function of the epithelium and thereby render the underlying airway smooth muscle more accessible to aerosolized methacholine. The PLL-treated animals were hypersensitive to methacholine: they exhibited an exaggerated response to submaximal doses but had a maximal response that was similar to controls. With the aid of a computational model of the mouse lung, we conclude that the methacholine responsiveness of PLL-treated mice is fundamentally different in nature to the hyperresponsiveness that we found previously in mice with allergically inflamed lungs.     

Effect of transpulmonary pressure on airway diameter and responsiveness of immature and mature rabbits.

We previously demonstrated that airway responsiveness is greater in immature than in mature rabbits; however, it is not known whether there are maturational differences in the effect of transpulmonary pressure (Ptp) on airway size and airway responsiveness. The relationship between Ptp and airway diameter was assessed in excised lungs insufflated with tantalum powder. Diameters of comparable intraparenchymal airway segments were measured from radiographs obtained at Ptp between 0 and 20 cmH(2)O. At Ptp > 8 cmH(2)O, the diameters were near maximal in both groups. With diameter normalized to its maximal value, changing Ptp between 8 and 0 cmH(2)O resulted in a greater decline of airway caliber in immature than mature airways. The increases in lung resistance (RL) in vivo at Ptp of 8, 5, and 2 cmH(2)O were measured during challenge with intravenous methacholine (MCh: 0.001-0.5 mg/kg). At Ptp of 8 cmH(2)O, both groups had very small responses to MCh and the maximal fold increases in RL did not differ (1.93 +/- 0.29 vs. 2.23 +/- 0.19). At Ptp of 5 and 2 cmH(2)O, the fold increases in RL were greater for immature than mature animals (13.19 +/- 1.81 vs. 3.89 +/- 0.37) and (17.74 +/- 2.15 vs. 4.6 +/- 0.52), respectively. We conclude that immature rabbits have greater airway distensibility and this difference may contribute to greater airway narrowing in immature compared with mature rabbits.     

Prostaglandin F2α increases responsiveness of pulmonary airways in dogs

We studied the effect of prostaglandin F_2α (PGF_2α) on the responsiveness of pulmonary airways in dogs. Airway responsiveness was assessed by determining the bronchoconstrictor response to increasing concentrations of acetylcholine aerosol delivered to the airways. In each of five dogs, we determined responsiveness during treatment with physiologic saline, histamine, or PGF_2α aerosols. The doses of histamine and PGF_2α were determined by establishing the largest dose of each which could be given to the dog without causing bronchoconstriction (subthreshold doses). We found that airway responsiveness was not significantly different during histamine treatment than after saline, however, responsiveness increased during treatment with PGF_2α. In addition, the hyperresponsiveness induced by PGF_2α was prevented by pretreatment with the ganglion blocking drug hexamethonium (5 mg/kg given intravenously). The results show that PGF_2α specifically increases the responsiveness of pulmonary airways in doses that do not cause bronchoncostriction, and suggest that the hyperresponsiveness involves a neural mechanism such as increased responsiveness of airway sensory nerves.