Lemakalim attenuates hypocapnia- and dry air-induced bronchoconstriction in canine peripheral airways

1993 ◽  
Vol 75 (1) ◽  
pp. 86-92 ◽  
Author(s):  
K. S. Lindeman ◽  
A. N. Freed
Keyword(s):  
Airway Resistance ◽  
Channel Blocker ◽  
K Channel ◽  
Dry Air ◽  
Peripheral Airways ◽  
Airway Constriction ◽  
Before And After ◽  
Peripheral Airway ◽  
Anesthetized Dogs ◽  
K Channel Opener

To determine the effect of changes in potassium (K+) flux on airway constriction, we studied effects of lemakalim, a K+ channel opener, and glibenclamide, an ATP-sensitive K+ channel blocker. A wedged bronchoscope technique was used to measure peripheral airway resistance (Rp) in anesthetized dogs. Rp was measured before and after constriction of the airways by hypocapnic challenge, acetylcholine aerosol, or dry air hyperpnea. Lemakalim (5 micrograms/kg i.v.) was administered, and the challenge was repeated. Lemakalim attenuated responses to hypocapnia by 72 +/- 7% (n = 6, P = 0.0007) and to dry air challenge by 37 +/- 8% (n = 6, P = 0.005) but not to acetylcholine. On separate days, sublobar segments were pretreated with aerosolized glibenclamide (2 mg/ml), and responses to hypocapnic challenge were measured before and after lemakalim (5 micrograms/kg i.v.), nifedipine (20 micrograms/kg i.v.), or albuterol (1 microgram/kg i.v.). In the presence of glibenclamide, lemakalim had no significant effect on responses to hypocapnia; however, both nifedipine (n = 6, P = 0.0003) and albuterol (n = 6, P = 0.0001) attenuated responses to hypocapnic challenge. These findings suggest that lemakalim attenuated hypocapnic bronchoconstriction by promoting K+ efflux through ATP-sensitive K+ channels.

A beta 2-adrenergic agonist inhibits dry air-induced injury in canine peripheral airways

1995 ◽  
Vol 78 (6) ◽  
pp. 2169-2179 ◽  
Author(s):  
C. Omori ◽  
B. H. Schofield ◽  
W. Mitzner ◽  
A. N. Freed
Keyword(s):  
Airway Resistance ◽  
Ciliated Cell ◽  
Mucosal Damage ◽  
Mast Cell Degranulation ◽  
Adrenergic Agonist ◽  
Dry Air ◽  
Peripheral Airways ◽  
Peripheral Airway ◽  
Anesthetized Dogs ◽  
Beta 2

We examined the effects of a beta 2-agonist on dry air-induced injury in canine peripheral airways. Dry air-induced bronchoconstriction (AIB) was assessed by measuring peripheral airway resistance in anesthetized dogs. Salbutamol reduced AIB by approximately 75% compared with control values. Colloidal carbon was used to detect bronchovascular leakage in contralateral sublobar segments that were pretreated with saline or salbutamol. About 87% of the perimeter of bronchi was damaged after dry air challenge in saline-treated segments. Salbutamol reduced mucosal damage by approximately 30% (P < 0.05). The mucosa of bronchioles was not injured. The average goblet-to-ciliated cell ratio (which reflects mucosal perturbation) in bronchi decreased from 0.38 in control bronchi to 0.15 in challenged bronchi, and this effect was also evident in bronchioles. Salbutamol did not affect this decrement. Dry air challenge also caused degranulation of mast cells located below damaged mucosa, dilation of bronchial vessels, and leakage from capillaries and venules located below normal ciliated and damaged mucosa of bronchi. Thus, we conclude that salbutamol attenuates epithelial damage and AIB but fails to inhibit mast cell degranulation and vascular hyperpermeability.

Mucosal injury and eicosanoid kinetics during hyperventilation-induced bronchoconstriction

1999 ◽  
Vol 87 (5) ◽  
pp. 1724-1733 ◽  
Author(s):  
Arthur N. Freed ◽  
Yongqiang Wang ◽  
Sharron McCulloch ◽  
Teresa Myers ◽  
Ryoichi Suzuki
Keyword(s):  
Epithelial Cells ◽  
Mucosal Injury ◽  
Mucosal Damage ◽  
Mediator Release ◽  
Moist Air ◽  
Dry Air ◽  
Peripheral Airways ◽  
Airway Constriction ◽  
Peripheral Airway ◽  
Balf Cell

Bronchoalveolar lavage (BAL) of canine peripheral airways was performed at various times after hyperventilation, and BAL fluid (BALF) cell and mediator data were used to evaluate two hypotheses: 1) hyperventilation-induced mucosal injury stimulates mediator production, and 2) mucosal damage is correlated with the magnitude of hyperventilation-induced bronchoconstriction. We found that epithelial cells increased in BALF immediately after a 2- and a 5-min dry air challenge (DAC). Prostaglandins D2 and F2α and thromboxane B2 were unchanged immediately after a 2-min DAC but were significantly increased after a 5-min DAC. Leukotriene C4, D4, and E4 did not increase until 5 min after DAC. Hyperventilation with warm moist air did not alter BALF cells or mediators and caused less airway obstruction that occurred earlier than DAC. BALF epithelial cells were correlated with mediator release, and mediator release and epithelial cells were correlated with hyperventilation-induced bronchoconstriction. These observations are consistent with the hypothesis that hyperventilation-induced mucosal damage initiates peripheral airway constriction via the release of biochemical mediators.

Eicosanoids modulate hyperpnea-induced bronchoconstriction in canine peripheral airways

1996 ◽  
Vol 81 (3) ◽  
pp. 1255-1263 ◽  
Author(s):  
C. Omori ◽  
P. Tagari ◽  
A. N. Freed
Keyword(s):  
Bronchoalveolar Lavage ◽  
Wall Temperature ◽  
Airway Resistance ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Airway Wall ◽  
Airway Reactivity ◽  
Dry Air ◽  
Peripheral Airways ◽  
Peripheral Airway

We examined the role of leukotrienes (LTs) in the development of dry air-induced bronchoconstriction (AIB) in canine peripheral airways. Airway reactivity to exogenous LTs was first tested by using an LTD4 aerosol challenge: peripheral airway resistance increased approximately 130 +/- 51% (n = 4) above baseline when compared with its vehicle control. AIB was then assessed by measuring peripheral airway resistance after, and airway wall temperature during, a dry air challenge (DAC). Treatment with a peptidoleukotriene biosynthesis inhibitor (MK-0591) attenuated AIB by approximately 65% without altering airway wall temperature. The fact that MK-0591 did not alter airway reactivity to aerosolized acetylcholine and completely inhibited Ca2+ ionophore-induced LTB4 generation in canine whole blood attests to the specificity of the drug. Treatment with MK-0591 did not affect the increased number of epithelial cells recovered in bronchoalveolar lavage fluid 5 min after DAC. Concentrations of LTs and other eicosanoids in bronchoalveolar lavage fluid from vehicle-treated DAC airways were increased above baseline values; only LTs were reduced by MK-0591. Before MK-0591, AIB was significantly correlated with the dry air-induced generation of LTC4, LTD4, and LTE4. After treatment with MK-0591, AIB was correlated with thromboxane B2, prostaglandin (PG) F2 alpha, and PGE2. We conclude that hyperpnea with dry air stimulates local production and release of LTs in canine bronchi and, alone with the generation of bronchoconstricting and bronchodilating PGs, plays a central role in the modulation of AIB.

Dry air-induced constriction in lung periphery: a canine model of exercise-induced asthma

1985 ◽  
Vol 59 (6) ◽  
pp. 1986-1990 ◽  
Author(s):  
A. N. Freed ◽  
B. Bromberger-Barnea ◽  
H. A. Menkes
Keyword(s):  
Flow Rate ◽  
Exposure Period ◽  
Canine Model ◽  
Base Line ◽  
Dry Air ◽  
Peripheral Airways ◽  
Before And After ◽  
Anesthetized Dogs ◽  
Lung Periphery ◽  
Exercise Induced

We studied the effects of the flow of dry air on collateral tone in the lung periphery. A bronchoscope was wedged in sublobar segments of anesthetized dogs, and measurements of collateral resistance (Rcs) were recorded before and after flow was increased from 200 to 2,000 ml/min for a 5-min period. Five minutes after exposure was completed, Rcs increased by an average of 117 +/- 25.2% (SE) over control. Maximum Rcs occurred 5 min after the challenge was concluded and required 48 +/- 10.5 min to return to base line. When flow rate was held constant and exposure period varied, Rcs increased with increased stimulus duration. With exposure times held constant, the response of the collateral system was positively associated with changes in stimulus strength (flow rate). No refractory period was observed with repetitive challenges. Finally, when dry air (delivered at 22 degrees C) and conditioned air (i.e., delivered at 28 degrees C; relative humidity = 80%) challenges were alternated in the same wedged segment, dry air produced a mean increase in Rcs of 93.2%, whereas challenge with warm moist air increased Rcs only 33.5%. Regardless of which challenge was presented first, dry air consistently produced a greater constrictor response. This response is similar to that observed in cold air- and exercise-induced asthma and indicates that the lung periphery in dogs, like larger airways in asthmatic subjects, has the potential to increase tone when exposed to dry air. Peripheral airways in dogs thus constitute a model that can be used for the investigation of exercise-induced asthma.

Hyperpnea with dry air causes time-dependent alterations in mucosal morphology and bronchovascular permeability

1995 ◽  
Vol 78 (3) ◽  
pp. 1043-1051 ◽  
Author(s):  
C. Omori ◽  
B. H. Schofield ◽  
W. Mitzner ◽  
A. N. Freed
Keyword(s):  
Airway Resistance ◽  
Ciliated Cell ◽  
Mucosal Injury ◽  
Cell Number ◽  
Physiological Changes ◽  
Dry Air ◽  
Peripheral Airways ◽  
Peripheral Airway ◽  
Mast Cell Number ◽  
Mucosal Morphology

This study examines the morphological and physiological changes that occur in canine peripheral airways after hyperpnea with dry air. Peripheral airways were exposed to a 5-min 2,000 ml/min dry air challenge (DAC) at 24, 6, 2, or 1 h before or 60 s after (0 h) the injection of colloidal carbon. After recording the dry air-induced increase in peripheral airway resistance, the lungs were removed and prepared for morphometric analysis (n = 5). Light microscopy revealed that 50% of the airway perimeter appeared damaged at 0, 1, and 2 h after DAC, and repair was evident 6–24 h after the challenge. The average goblet-to-ciliated cell ratio decreased from 0.34 before DAC to 0.15 after DAC and recovered within 24 h. Dry air-induced bronchovascular leakage occurred immediately after DAC and persisted for > or = 24 h. DAC decreased mast cell number only in regions where the mucosa was damaged, and this decrease was inversely correlated with bronchovascular leakage. Finally, leukocyte infiltration was evident 1–2 h after DAC and continued throughout the 24-h period. We conclude that hyperpnea with dry air causes mucosal injury, inflammation, and microvascular leakage and that these dry air-induced effects persist for > or = 24 h after DAC.

Dose-response curves of central and peripheral airways to nicotine injections in dogs

1986 ◽  
Vol 61 (5) ◽  
pp. 1677-1685 ◽  
Author(s):  
M. Nakamura ◽  
T. Haga ◽  
M. Miyano ◽  
H. Sasaki ◽  
T. Takishima
Keyword(s):  
Dose Response ◽  
Airway Resistance ◽  
Suppressive Effect ◽  
Response Curves ◽  
Parasympathetic Ganglia ◽  
Peripheral Airways ◽  
Peripheral Airway ◽  
Anesthetized Dogs ◽  
Vagal Reflex ◽  
Dose Response Curves

The dose-response curves of the central and peripheral airways to intravenously injected nicotine were studied in 55 anesthetized dogs. With intact vagi, nicotine caused a dose-dependent increase in central airway resistance (Rc) similar to the increase in peripheral airway resistance (Rp) at concentrations ranging from 4 to 64 micrograms/kg. However, the responses of both Rc and Rp fell progressively when sequential doses of nicotine greater than 256 micrograms/kg were administered. With intact vagi and the administration of propranolol, there was a greater increase in Rp than in Rc at a nicotine dose of 64 micrograms/kg (P less than 0.05). With vagotomy, the responsiveness of both central and peripheral airways to nicotine decreased with doses of nicotine less than 64 micrograms/kg, but with doses of nicotine greater than 256 micrograms/kg the suppressive effect of nicotine on both Rc and Rp was less than that seen with intact vagi. Under conditions in which the vagi were cut and atropine administered, the responsiveness of nicotine was even further depressed. Combinations either of atropine and chlorpheniramine or atropine and phenoxybenzamine also completely blocked reactions to nicotine. Additionally reactions to nicotine were completely blocked by hexamethonium. These results suggest that nicotine increases both Rc and Rp mainly through a vagal reflex and stimulation of the parasympathetic ganglia.

ATP-sensitive K+ channel opener pinacidil augments beta 1-adrenoceptor-induced coronary vasodilation in dogs

1996 ◽  
Vol 270 (6) ◽  
pp. H2210-H2215 ◽  
Author(s):  
Y. Katsuda ◽  
K. Egashira ◽  
H. Ueno ◽  
Y. Arai ◽  
Y. Akatsuka ◽  
...  
Keyword(s):  
Metabolic Stress ◽  
K Channel ◽  
Coronary Vasodilation ◽  
Beta Adrenoceptor ◽  
Intracoronary Infusion ◽  
Channel Opener ◽  
Adrenoceptor Agonist ◽  
Anesthetized Dogs ◽  
Beta 2 ◽  
K Channel Opener

The opening of ATP-sensitive K+ (K+ATP) channels contributes to the mechanism of metabolic coronary vasodilation. The aim of the present study was to determine whether K+ATP channel opener pinacidil augments coronary vasodilation induced by beta-adrenoceptor stimulation. In anesthetized dogs, coronary vasodilation in response to intracoronary infusion of a beta 1-adrenoceptor agonist denopamine, selective beta 2-adrenoceptor stimulation with isoproterenol after bisoprolol or nitroglycerin was studied before and during simultaneous intracoronary infusion of pinacidil at a dose of 1 microgram/min, which had no effect on basal hemodynamics. Pinacidil augmented the denopamine-induced increase in coronary blood flow (CBF) from 38 +/- 9 to 66 +/- 16% (P < 0.05) but did not affect the denopamine-induced by isoproterenol or nitroglycerin. Thus pinacidil selectively augmented beta 1-adrenoceptor-mediated coronary vasodilation. These observations suggest that the K+ATP channel opener pinacidil may increase myocardial perfusion during metabolic stress associated with beta 1-adrenoceptor stimulation.

Effect of regional inhomogeneity on collateral airway resistance

1984 ◽  
Vol 57 (1) ◽  
pp. 254-261 ◽  
Author(s):  
S. D. Fuller ◽  
N. E. Robinson
Keyword(s):  
Airway Resistance ◽  
Transpulmonary Pressure ◽  
Double Lumen ◽  
Double Lumen Catheter ◽  
Lung Segment ◽  
Peripheral Airway ◽  
Lumen Catheter ◽  
Anesthetized Dogs ◽  
Relationship Of ◽  
Regional Inhomogeneity

We studied the interaction of transpulmonary pressure (Pao) and the pressure in an isolated sublobar lung segment (Ps) on collateral resistance (Rcoll) in excised dog lungs. A double-lumen catheter was advanced through the trachea and wedged in a peripheral airway. Gas flowed through the outer lumenof the catheter (Vcoll) to enter the segment while Ps was measured by the inner lumen. Collateral resistance was calculated as Rcoll = (Ps - Pao)/Vcoll. At constant Ps, raising Pao sharply decreased Rcoll, but at constant Pao, raising Ps increased Rcoll. Replotting these data showed that Rcoll was related to the pressure difference between the segment and the remainder of the lobe (Ps - Pao), such that raising Ps - Pao caused no change in Rcoll at lower Pao but increased Rcoll at higher Pao. Similarfindings occurred in the lungs of closed-chest anesthetized dogs. We propose that this technique measures the sum of resistances of airways and collateral channels found in the segment body (Rs) and of those passing through the segment-lobar parenchymal interface (Ri). Raising Ps - Pao decreases Rs because of the volume dependency of airway resistance and increases Ri due to tissue distortion at the interface occurring as a result of inhomogeneous segment inflation. The net change in measured Rcoll depends on which of its components change in greatest magnitude. This effect varies with Pao due to thehyperbolic relationship of Pao with airway and collateral resistance.

Interaction of sulfur dioxide and dry cold air in causing bronchoconstriction in asthmatic subjects

1984 ◽  
Vol 57 (2) ◽  
pp. 419-423 ◽  
Author(s):  
R. A. Bethel ◽  
D. Sheppard ◽  
J. Epstein ◽  
E. Tam ◽  
J. A. Nadel ◽  
...  
Keyword(s):  
Sulfur Dioxide ◽  
Room Temperature ◽  
Airway Resistance ◽  
Random Order ◽  
Gas Mixtures ◽  
Cold Air ◽  
Dry Air ◽  
Specific Airway Resistance ◽  
Blinded Study ◽  
Before And After

To determine whether sulfur dioxide and airway cooling and drying interact in causing bronchoconstriction in persons who have asthma, we measured specific airway resistance in seven asthmatic subjects before and after they performed voluntary eucapnic hyperpnea for 3 min breathing four different gas mixtures. The mixtures, which the subjects breathed through a mouthpiece in random order on 4 different days, were 1) humidified room-temperature air, 2) humidified room-temperature air containing 0.5 ppm SO2, 3) cold dry air, and 4) cold dry air containing 0.5 ppm SO2. Each subject breathed at a rate and depth known from preliminary studies to cause little or no bronchoconstriction when that subject inhaled 0.5 ppm SO2 in humidified room-temperature air or cold dry air. When given independently in the blinded study, 0.5 ppm SO2 or cold dry air again caused insignificant bronchoconstriction, but when given together the two stimuli caused significant bronchoconstriction, as indicated by an increase in specific airway resistance from 6.94 +/- 2.85 to 22.35 +/- 10.28 l X cmH2O X l–1 X s (mean +/- SD) (P less than 0.001). thus airway cooling and/or drying increases the bronchoconstriction induced by inhaled SO2 in persons who have asthma. This increase suggests that persons who have asthma may be more sensitive to the bronchoconstrictor effects of ambient SO2 in cold dry environments than in warm moist environments.

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