Histamine and leukotrienes mediate pulmonary hypersensitivity to antigen in guinea pigs

1984 ◽  
Vol 56 (4) ◽  
pp. 1032-1038 ◽  
Author(s):  
W. J. Lamm ◽  
Y. L. Lai ◽  
J. Hildebrandt
Keyword(s):  
Guinea Pigs ◽  
Minute Ventilation ◽  
Dynamic Compliance ◽  
Systemic Arterial Pressure ◽  
Antigen Challenge ◽  
Base Line ◽  
Treatment Groups ◽  
Airway Responses ◽  
Experimental Values ◽  
Line P

To study roles of histamine and slow-reacting substance of anaphylasis (SRS-A) in mediating airway responses following antigen challenge, mediator antagonists were administered to guinea pigs sensitized with ovalbumin 10 days before the study. Twenty-three animals were divided into the following five treatment groups: 1) saline only (control 1, n = 5); 2) antigen challenged (n = 5); 3) antigen + methapyrilene (antihistamine, n = 5); 4) FPL 55712 only (SRS-A antagonist, control 2; n = 4), and 5) antigen + FPL 55712 (n = 4). Control groups were not sensitized. Experimental values were compared with those of control 1 at equal times after injections. Pulmonary resistance (RL), dynamic compliance (Cdyn), breathing frequency (f), tidal volume, minute ventilation (VE) and systemic arterial pressure were measured for 15–20 min just before (base line) and for up to 30 min after saline or antigen administration. Antigen challenge alone induced maximal respiratory changes at 5 min. RL increased 131 +/- 28% above base line (P less than 0.05), whereas Cdyn decreased slightly (28 +/- 10%, P less than 0.05). Antihistamine almost eliminated all changes in RL but did not affect decreased Cdyn. On the other hand, FPL 55712 eliminated changes in both RL and Cdyn. Both antagonists blocked the transient increase in VE, but neither blocked the rise in f at 5 min. We conclude that antigen-induced bronchoconstriction (RL) may be primarily mediated by histamine, whereas simultaneous alterations in Cdyn may depend mainly on leukotrienes and those in f depend on neither.

Bronchoconstriction elicited by isocapnic hyperpnea in guinea pigs

1988 ◽  
Vol 65 (2) ◽  
pp. 934-939 ◽  
Author(s):  
D. W. Ray ◽  
C. Hernandez ◽  
N. Munoz ◽  
A. R. Leff ◽  
J. Solway
Keyword(s):  
Tidal Volume ◽  
Guinea Pigs ◽  
Room Temperature ◽  
Time Course ◽  
Minute Ventilation ◽  
Recovery Period ◽  
Dynamic Compliance ◽  
Base Line ◽  
Stimulus Response ◽  
Airway Response

We demonstrated spontaneous self-limited bronchoconstriction after eucapnic dry gas hyperpnea in 22 anesthetized, mechanically ventilated guinea pigs pretreated with propranolol (1 mg/kg iv). Eucapnic hyperpnea "challenges" of room temperature dry or humidified gas (5% CO2-95% O2) were performed by mechanically ventilating animals (150 breaths/min, 3-6 ml tidal volume) for 5 min. During a "recovery" period after hyperpnea, animals were returned to standard ventilation conditions (6 ml/kg, 60 breaths/min, 50% O2 in air, fully saturated at room temperature). After dry gas hyperpnea (5 ml, 150 breaths/min), respiratory system resistance (Rrs) increased in the recovery period by 7.7-fold and dynamic compliance (Cdyn) decreased by 79.7%; changes were maximal at approximately 3 min posthyperpnea and spontaneously returned to base line in 10-40 min. This response was markedly attenuated by humidification of inspired air. Four consecutive identical dry air challenges resulted in similar posthyperpnea responses in four animals. Increasing the minute ventilation during hyperpnea (by varying tidal volume from 3 to 6 ml) caused increased bronchoconstriction in a dose-dependent fashion in six animals. Neither vagotomy nor atropine altered the airway response to dry gas hyperpnea. We conclude that dry gas hyperpnea in anesthetized guinea pigs results in a bronchoconstrictor response that shares five similar features with hyperpnea-induced bronchoconstriction in human asthma: 1) time course of onset and spontaneous resolution, 2) diminution with humidification of inspired gas, 3) reproducibility on consecutive identical challenges, 4) stimulus-response relationship with minute ventilation during hyperpnea, and 5) independence of parasympathetic neurotransmission.

Effect of the NEP inhibitor SCH32615 on airway responses to intravenous substance P in guinea pigs

1992 ◽  
Vol 73 (5) ◽  
pp. 1847-1853 ◽  
Author(s):  
S. A. Shore ◽  
M. A. Martins ◽  
J. M. Drazen
Keyword(s):  
Substance P ◽  
Guinea Pigs ◽  
Ace Inhibitor ◽  
Dynamic Compliance ◽  
Neutral Endopeptidase ◽  
Neurokinin A ◽  
Mechanically Ventilated ◽  
Arterial Blood ◽  
Airway Responses ◽  
Nep Inhibition

We examined the effects of the selective neutral endopeptidase (NEP) inhibitor SCH32615 on airway responses to rapid intravenous infusions of substance P (SP) and neurokinin A (NKA) and on recovery of administered tachykinins from arterial blood in anesthetized mechanically ventilated guinea pigs. SCH32615, in doses that cause a marked increase in the magnitude of bronchoconstriction induced by infused NKA, had little effect on the changes in pulmonary conductance (GL) or dynamic compliance induced by SP. In animals in which SCH32615 (1 mg/kg) was administered in combination with the angiotensin-converting enzyme (ACE) inhibitor captopril (5.7 mg/kg), the dose of SP required to decrease GL by 50% was fourfold less than in animals that received captopril alone (P < 0.005). SP measured in arterial blood withdrawn within 45 s of intravenous administration of this tachykinin was not different in control and SCH32615-treated animals, whereas captopril caused an approximately threefold increase in SP concentrations (P < 0.005). When SCH32615 and captopril were administered together, significantly more SP was recovered than when captopril or SCH32615 was administered alone (P < 0.0005). Our results are consistent with the hypothesis that both NEP and ACE contribute to the degradation of intravenously infused SP. ACE degradation of SP is sufficient to limit SP-induced bronchoconstriction even in the presence of specific NEP inhibition.

Effect of granulocyte depletion on altered lung mechanics after endotoxemia in sheep

1983 ◽  
Vol 55 (1) ◽  
pp. 92-99 ◽  
Author(s):  
J. M. Hinson ◽  
A. A. Hutchison ◽  
M. L. Ogletree ◽  
K. L. Brigham ◽  
J. R. Snapper
Keyword(s):  
Dynamic Compliance ◽  
Lung Mechanics ◽  
Arterial Oxygen ◽  
Base Line ◽  
Mean Pulmonary Arterial Pressure ◽  
Before And After ◽  
Airway Response ◽  
Pulmonary Arterial ◽  
Line P

To examine the role of circulating granulocytes in the airway changes caused by endotoxemia, we measured the response of chronically instrumented unanesthetized sheep to endotoxemia before and after granulocyte depletion with hydroxyurea. Granulocyte depletion did not affect the increases in mean pulmonary arterial pressure caused by endotoxin [peak pressure 59 +/- 8 cmH2O +/- (SE) control, 51 +/- 8 cmH2O granulocyte depleted]. However, the early (30-60 min after endotoxin) airway response to endotoxemia was markedly attenuated. Without granulocyte depletion, endotoxin caused dynamic compliance (Cdyn) to decrease to 41 +/- 10% of the base-line value and total lung resistance (RL) to increase to 283 +/- 61% of base line. When animals were granulocyte depleted, endotoxin decreased Cdyn to 69 +/- 6% (P less than 0.05) of base line and increased RL to 141 +/- 20% of base line (P less than 0.05). Granulocyte depletion also attenuated the effect of endotoxin on arterial oxygenation. During the maximum airway response to endotoxin, the alveolar-to-arterial oxygen gradient was 47 +/- 5 Torr in control studies and 32 +/- 2 Torr in granulocyte depleted studies (P less than 0.05). We conclude that interaction of granulocytes with the lung contributes to the changes in lung mechanics observed following endotoxemia and that the early pulmonary hypertension and the early alterations in lung mechanics caused by endotoxemia are caused by separate processes.

Histamine dose-response curves in guinea pigs

1985 ◽  
Vol 58 (2) ◽  
pp. 625-634 ◽  
Author(s):  
W. C. Hulbert ◽  
T. McLean ◽  
B. Wiggs ◽  
P. D. Pare ◽  
J. C. Hogg
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Response Curve ◽  
Dynamic Compliance ◽  
Dose Response Curve ◽  
Base Line ◽  
Response Curves ◽  
Mechanically Ventilated ◽  
Dose Response Curves ◽  
The Right

Histamine dose-response curves were performed on anesthetized tracheostomized guinea pigs that were paralyzed and mechanically ventilated at a constant tidal volume and breathing frequency. The dose was calculated by generating an aerosol of known concentration and measuring the volume delivered to the lung. Increasing the dose was accomplished by increasing the number of breaths of aerosol delivered. The response to each dose was determined by measuring the change in airway resistance (RL) and dynamic compliance (Cdyn) using the method of Von Neergaard and Wirz (Z. Klin. Med. 105: 51–82, 1927). With increasing doses of histamine, RL increased and reached a plateau at approximately five times the base-line value and Cdyn fell to approximately 20% of its initial value. The variability in the base-line and maximum response as well as the calculated sensitivity and reactivity was less than that previously reported. Propranolol pretreatment increased resting RL and shifted the dose-response curve for RL to the left of the controls, increasing reactivity but not sensitivity. Atropine shifted the dose-response curve to the right of the control, decreasing sensitivity but without changing reactivity. The data for Cdyn showed that atropine pretreatment caused a higher resting value and propranolol pretreatment a lower value at the highest histamine dose but no differences in either sensitivity or reactivity.

Tachyphylaxis to inhaled aerosolized histamine in anesthetized dogs

1985 ◽  
Vol 59 (5) ◽  
pp. 1355-1363 ◽  
Author(s):  
S. Shore ◽  
J. G. Martin
Keyword(s):  
Dose Response ◽  
Dynamic Compliance ◽  
Pulmonary Mechanics ◽  
Base Line ◽  
Response Curves ◽  
Low Concentrations ◽  
Anesthetized Dogs ◽  
Dose Response Curves ◽  
High Concentrations ◽  
Airway Responses

Three consecutive dose-response curves to inhaled aerosolized histamine, separated by 1-h intervals, were obtained in 20 anesthetized mongrel dogs. In general, successive histamine dose-response curves shifted progressively rightward. Changes in pulmonary resistance (RL) and dynamic compliance (Cdyn) in response to low concentrations of histamine were reproducible, but responses to high concentrations (sufficient to at least double RL or decrease Cdyn by at least 30%) decreased on successive dose-response curves. The concentration of histamine required to double RL increased significantly (P less than 0.05) from 1.01 mg/ml on the first to 1.62 and 2.02 mg/ml on the second and third dose-response curves. In contrast, consecutive methacholine dose-response curves were not significantly different. Indomethacin pretreatment (5 mg/kg iv) prevented histamine tachyphylaxis, whereas atropine (4 mg iv) did not. However, indomethacin did not alter base-line pulmonary mechanics or histamine responsiveness as measured on the first dose-response curve. We conclude that tachyphylaxis to inhaled aerosolized histamine occurs in anesthetized dogs. Our results are consistent with an important role for endogenous prostaglandins in modulating the airway responses to repeated histamine exposures.

A possible role for PAF in allergen-induced late responses: modification by a selective antagonist

1989 ◽  
Vol 66 (5) ◽  
pp. 2351-2357 ◽  
Author(s):  
W. M. Abraham ◽  
J. S. Stevenson ◽  
R. Garrido
Keyword(s):  
Dose Range ◽  
Platelet Activating Factor ◽  
Early Response ◽  
Base Line ◽  
Leukotriene D4 ◽  
Leukotriene Antagonist ◽  
Airway Responses ◽  
H1 Antagonist ◽  
Line P ◽  
Web 2086

We determined whether platelet-activating factor (PAF) plays a role in allergen-induced airway responses by studying the effects of a selective PAF antagonist WEB-2086 on antigen-induced early and late airway responses in allergic sheep. In seven sheep, inhaled Ascaris suum produced significant early (282%) and late (176%) increases in specific lung resistance (sRL). WEB-2086 (1 mg/kg iv) given 20 min before antigen challenge did not affect the early response, but the peak late increase in sRL was only 37% over base line (P less than 0.05 vs. control). To study the mechanism by which PAF contributes to antigen-induced responses, we evaluated the effects of pharmacological probes on PAF-induced bronchoconstriction. Inhaled PAF (dose range 75–700 micrograms) caused reproducible (r = 0.781, P less than 0.05) increases in sRL in eight sheep. The PAF-induced bronchoconstriction was blocked by WEB-2086 (1 mg/kg iv) and by the leukotriene antagonist FPL-55712 (30 mg by aerosol); however, neither the cyclooxygenase blocker indomethacin (2 mg/kg iv) nor the histamine H1-antagonist chlorpheniramine (2 mg/kg iv) blocked the PAF response. WEB-2086, however, did not block bronchoconstriction induced by aerosol leukotriene D4, indicating that PAF acts indirectly through leukotrienes. Finally, we determined whether PAF could induce late airway responses. Inhaled PAF produced an immediate increase in sRL in all seven sheep tested, but late airway responses were observed in only three of the seven sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Bronchial responses to substance P after antigen challenge in the guinea-pig: in vivo and in vitro studies

1992 ◽  
Vol 1 (3) ◽  
pp. 207-212 ◽  
Author(s):  
E. Boichot ◽  
V. Lagente ◽  
G. Le Gall ◽  
C. Carré ◽  
J. M. Mencia-Huerta ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Bronchial Hyperresponsiveness ◽  
Neutral Endopeptidase ◽  
Antigen Challenge ◽  
Control Groups ◽  
Airway Responses

The effect of antigen challenge on the airway responses to substancePand on the epithelial neutral endopeptidase (NEP) activity was investigated in aerosol sensitized guinea-pigs. In vivo, bronchial responses to aerosolized substancePwere similar to the responses observed in antigen-challenged guinea-pigs and in the control groups. In contrast, when the guinea-pigs were pretreated with the NEP inhibitor, phosphoramidon, a significant increase in the airway responses to substancePwas observed after antigen challenge in vivo. However, in vitro, the contractile responses of the tracheal smooth muscle to substancePwere similar between groups of guinea-pigs, in respect to the presence or absence of the epithelium and/or phosphoramidon. Histological studies showed an accumulation of eosinophils in the tracheal submucosa after antigen challenge and intact epithelial cells. These results show that in vivo bronchial hyperresponsiveness to substancePafter antigen challenge in the guinea-pig is not associated with increased responses of the smooth muscle to exogenousSPin vitro. In addition, the results with phosphoramidon suggest that loss of NEP activity cannot account for the in vivo bronchial hyperresponsiveness to substancePpresently observed.

Enhanced airway responses to substance P after repeated challenge in guinea pigs

1989 ◽  
Vol 66 (2) ◽  
pp. 955-961 ◽  
Author(s):  
S. A. Shore ◽  
J. M. Drazen
Keyword(s):  
Substance P ◽  
Dose Response ◽  
Guinea Pigs ◽  
Response Curve ◽  
Enzyme Inhibitor ◽  
Dose Response Curve ◽  
Base Line ◽  
Response Curves ◽  
Dose Response Curves ◽  
Airway Responses

We performed three consecutive dose-response curves to rapid intravenous infusions of substance P (SP) in anesthetized, mechanically ventilated guinea pigs. The dose of SP required to decrease pulmonary conductance to 50% of its base-line value (ED50GL) decreased 2.8-fold (P less than 0.002) and 3.3-fold (P less than 0.001) on the second and third dose-response curves, respectively, compared with the first. SP did not alter airway responses to intravenous histamine but did cause a significant (3.7-fold) decrease in ED50GL for dose-response curves to intravenous capsaicin, an agent that causes bronchoconstriction by release of endogenous tachykinins. The neutral metalloendopeptidase inhibitor thiorphan (0.5 mg) and the angiotensin-converting enzyme inhibitor captopril (1.7 mg) both caused a marked enhancement of airway responses to SP observed on the first dose-response curve but did not alter the enhancement of SP-induced airway responses produced by repeated SP challenge. The anticholinergic atropine (5 mg/kg iv), the antihistamine mepyramine (8 mg/kg iv), and the cyclooxygenase inhibitor indomethacin (30 mg/kg ip) had no effect on the first SP dose-response curve. Atropine and mepyramine did not prevent the enhancement of SP responses observed with repeated challenge, but after pretreatment with either indomethacin or acetylsalicylic acid, dose-response curves to SP were reproducible. Our results indicate that airway responses to intravenous SP are enhanced with repeated SP challenge and suggest that cyclooxygenase products of arachidonic acid metabolism are involved in the mediation of this phenomenon.

Relative bronchoconstrictor activity of neurokinin A and neurokinin A fragments in guinea pigs

1991 ◽  
Vol 71 (2) ◽  
pp. 452-457 ◽  
Author(s):  
S. A. Shore ◽  
J. M. Drazen
Keyword(s):  
Guinea Pigs ◽  
Time Course ◽  
Degradation Products ◽  
Rank Order ◽  
Dynamic Compliance ◽  
Neutral Endopeptidase ◽  
Neurokinin A ◽  
Duration Of Action ◽  
Airway Responses ◽  
Induced Changes

We examined the effect of rapid intravenous infusion of neurokinin A (NKA) and selected COOH-terminal NKA fragments on pulmonary conductance (GL) and dynamic compliance in anesthetized mechanically ventilated guinea pigs. The rank order of the dose of peptide required to reduce GL by 50% (ED50GL) was NKA = NKA2–10 = NKA3–10 = NKA4–10 less than NKA5–10 much less than NKA6–10. The time course of bronchoconstriction induced by NKA2–10, NKA3–10, and NKA4–10 was similar to that induced by NKA, whereas NKA5–10 and NKA6–10 each had a shorter duration of action than NKA for a similar induced maximal change in GL. To determine whether degradation of these NKA fragments by neutral endopeptidase (NEP) modulates their bronchoconstrictor activity as it does for native NKA, we examined the effect of the NEP inhibitor SCH32615 on NKA3–10-, NKA5–10-, and NKA6–10-induced changes in GL. We have previously reported that the ED50GL for NKA was approximately 20-fold lower in animals pretreated with SCH32615 (1 mg/kg) than in control guinea pigs. SCH32615 caused a 16-fold decrease in ED50GL for NKA3–10 (P less than 0.001) but had no effect on airway responses to NKA5–10 or NKA6–10. The results demonstrate that the magnitude and duration of bronchoconstriction induced by potential aminopeptidase degradation products of NKA are similar to those of the native peptide. Aminopeptidases do not, therefore, have the capacity to modulate the bronchoconstriction induced by this peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Noninvasive detection of airway constriction in awake guinea pigs

1984 ◽  
Vol 56 (6) ◽  
pp. 1666-1669 ◽  
Author(s):  
S. A. Silbaugh ◽  
J. L. Mauderly
Keyword(s):  
Tidal Volume ◽  
Guinea Pigs ◽  
Reference Signal ◽  
Dynamic Compliance ◽  
Base Line ◽  
Airway Narrowing ◽  
Simple Index ◽  
Airway Constriction ◽  
Compressibility Effects ◽  
Gas Compressibility

Tidal volume measured by the barometric method is very sensitive to increases in compression and expansion of alveolar gas, such as would be expected to occur during airway narrowing or closure. By comparing a barometric method tidal volume signal (VT′) with a reference tidal volume (VT) obtained with a head-out pressure plethysmograph, a simple index related to gas compressibility effects was calculated (VT/VT′). Changes in this index were compared with decreases in dynamic compliance (Cdyn) during histamine aerosol challenge of 15 Charles River Hartley guinea pigs. Decreases in VT/VT′ occurred during all aerosol challenges and were correlated with decreases in Cdyn (r = 0.84, P less than 0.001). Decreases in VT/VT′ were most marked at Cdyn values of less than 50% of base line. At Cdyn of less than 15% of base line, VT′ was 3.1–4.8 times the VT reference signal. No increase in total pulmonary resistance was noted, and Cdyn and VT/VT′ returned to base line after histamine exposure was stopped. We conclude that gas compressibility effects become substantial during histamine-induced airway constriction in the guinea pig and that the VT/VT′ ratio appears to provide a simple noninvasive method of detecting these changes.

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