scholarly journals Role of neutral endopeptidase in endotoxin-induced bronchial hyperresponsiveness to substance P in guinea pigs

1998 ◽  
Vol 47 (1) ◽  
pp. 13-22 ◽  
Author(s):  
Shigenori Iwamae ◽  
Hideo Tsukagoshi ◽  
Takeshi Hisada ◽  
Daisuke Uno ◽  
Masatomo Mori
Keyword(s):  
Substance P ◽  
Guinea Pigs ◽  
Bronchial Hyperresponsiveness ◽  
Neutral Endopeptidase

Role of tachykinins and neutral endopeptidase in toluene diisocyanate-induced bronchial hyperresponsiveness in guinea pigs

Toxicology ◽  
1997 ◽  
Vol 116 (1-3) ◽  
pp. 17-26 ◽  
Author(s):  
F. Gagnaire ◽  
M. Ban ◽  
C. Cour ◽  
J.C. Micillino ◽  
P. Bonnet ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Bronchial Hyperresponsiveness ◽  
Neutral Endopeptidase ◽  
Toluene Diisocyanate

Paradoxical effect of salbutamol in a model of acute organophosphates intoxication in guinea pigs: role of substance P release

2007 ◽  
Vol 292 (4) ◽  
pp. L915-L923 ◽  
Author(s):  
Jaime Chávez ◽  
Patricia Segura ◽  
Mario H. Vargas ◽  
José Luis Arreola ◽  
Edgar Flores-Soto ◽  
...  
Keyword(s):  
Substance P ◽  
Guinea Pigs ◽  
Smooth Muscle Contraction ◽  
In Vivo Experiments ◽  
Intracellular Ca ◽  
Neurokinin 1 ◽  
Substance P Release

Organophosphates induce bronchoobstruction in guinea pigs, and salbutamol only transiently reverses this effect, suggesting that it triggers additional obstructive mechanisms. To further explore this phenomenon, in vivo (barometric plethysmography) and in vitro (organ baths, including ACh and substance P concentration measurement by HPLC and immunoassay, respectively; intracellular Ca2+ measurement in single myocytes) experiments were performed. In in vivo experiments, parathion caused a progressive bronchoobstruction until a plateau was reached. Administration of salbutamol during this plateau decreased bronchoobstruction up to 22% in the first 5 min, but thereafter airway obstruction rose again as to reach the same intensity as before salbutamol. Aminophylline caused a sustained decrement (71%) of the parathion-induced bronchoobstruction. In in vitro studies, paraoxon produced a sustained contraction of tracheal rings, which was fully blocked by atropine but not by TTX, ω-conotoxin (CTX), or epithelium removal. During the paraoxon-induced contraction, salbutamol caused a temporary relaxation of ∼50%, followed by a partial recontraction. This paradoxical recontraction was avoided by the M2- or neurokinin-1 (NK1)-receptor antagonists (methoctramine or AF-DX 116, and L-732138, respectively), accompanied by a long-lasting relaxation. Forskolin caused full relaxation of the paraoxon response. Substance P and, to a lesser extent, ACh released from tracheal rings during 60-min incubation with paraoxon or physostigmine, respectively, were significantly increased when salbutamol was administered in the second half of this period. In myocytes, paraoxon did not produce any change in the intracellular Ca2+ basal levels. Our results suggested that: 1) organophosphates caused smooth muscle contraction by accumulation of ACh released through a TTX- and CTX-resistant mechanism; 2) during such contraction, salbutamol relaxation is functionally antagonized by the stimulation of M2 receptors; and 3) after this transient salbutamol-induced relaxation, a paradoxical contraction ensues due to the subsequent release of substance P.

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.

Tachykinin recovery during postmortem bronchoconstriction in guinea pig lungs

1991 ◽  
Vol 70 (3) ◽  
pp. 1215-1219 ◽  
Author(s):  
M. A. Martins ◽  
S. A. Shore ◽  
J. M. Drazen
Keyword(s):  
Substance P ◽  
Guinea Pig ◽  
Neutral Endopeptidase ◽  
Neurokinin A ◽  
Opening Pressure ◽  
Airway Opening ◽  
Isolated Lungs ◽  
Peak Value

We examined the role of substance P (SP) and neurokinin A (NKA) in the postmortem bronchoconstriction in guinea pig lungs using isolated lungs superfused via the trachea. Airway opening pressure (Pao) during superfusion was monitored and the superfusate collected for analysis of SP- and NKA-like immunoreactivities (SP-LI and NKA-LI, respectively). Peak Pao (39.0 +/- 3.9 cmH2O) was reached 10 min after starting superfusion; Pao decreased slowly thereafter, reaching only 9.9 +/- 2.2% of the peak value 2 h after starting superfusion (P less than 0.005); 12.6 +/- 2.6 and 34.0 +/- 9.7 fmol of SP-LI and NKA-LI, respectively, were found in the fraction corresponding to 10-20 min of superfusion. Recovered immunoreactivities decreased to 5.2 +/- 0.3 and 9.3 +/- 1.8 fmol of SP-LI and NKA-LI, respectively, in the fraction corresponding to 110-120 min of superfusion (P less than 0.05). Inhibition of neutral endopeptidase with thiorphan resulted in significantly greater increases in Pao (P less than 0.005) and augmentation of the recovery of SP-LI and NKA-LI (P less than 0.05 and P less than 0.001, respectively). Capsaicin treatment of animals 7-10 days before the removal of their lungs abolished the increase in Pao during superfusion and resulted in a significant decrease in the amount of SP-LI and NKA-LI recovered. Our data confirm that tachykinin release occurs during postmortem bronchoconstriction in guinea pig lungs and, furthermore, that tachykinin degradation by NEP modulates the intensity of this response.

Acute and chronic respiratory effects of sulfur mustard intoxication in guinea pig

1994 ◽  
Vol 76 (2) ◽  
pp. 681-688 ◽  
Author(s):  
J. H. Calvet ◽  
P. H. Jarreau ◽  
M. Levame ◽  
M. P. D′Ortho ◽  
H. Lorino ◽  
...  
Keyword(s):  
Substance P ◽  
Guinea Pigs ◽  
Sulfur Mustard ◽  
Neutral Endopeptidase ◽  
Chemical Warfare Agent ◽  
Airway Hyperreactivity ◽  
Tracheal Epithelium ◽  
Endopeptidase Activity ◽  
Respiratory System Resistance ◽  
Cell Shedding

Sulfur mustard (SM) has been used as a vesicant chemical warfare agent. To investigate the respiratory damages it causes, we studied the effects on guinea pigs of an intratracheal injection of 0.3 mg/kg of SM 5 h and 14 days after injection. Five hours after SM intoxication, respiratory system resistance and microvascular permeability were increased. These alterations were not prevented by pretreatment with 50 mg/kg sc of capsaicin 2 wk before SM intoxication. Histological studies showed columnar cell shedding all along the tracheal epithelium, bronchoconstriction, and peribronchial edema. Fourteen days after SM intoxication, guinea pigs demonstrated airway hyperreactivity to aerosolized substance P and histamine. Pretreatment with phosphoramidon caused a further increase in airway responsiveness to substance P. Neutral endopeptidase activity in the tracheal epithelium was decreased by twofold in SM-intoxicated guinea pigs. At this stage, the tracheal epithelium was disorganized and atrophic. These results demonstrate that in guinea pigs SM intoxication induces severe lesions to the tracheal epithelium, which might account for the airway hyperresponsiveness observed 14 days after intoxication.

Airway neutral endopeptidase-like enzyme modulates tachykinin-induced bronchoconstriction in vivo

1988 ◽  
Vol 65 (6) ◽  
pp. 2585-2591 ◽  
Author(s):  
D. J. Dusser ◽  
E. Umeno ◽  
P. D. Graf ◽  
T. Djokic ◽  
D. B. Borson ◽  
...  
Keyword(s):  
Substance P ◽  
Guinea Pig ◽  
Vagus Nerve ◽  
Nerve Stimulation ◽  
Guinea Pigs ◽  
Vagus Nerve Stimulation ◽  
Neutral Endopeptidase ◽  
Base Line ◽  
Pulmonary Resistance

To determine whether neutral endopeptidase (NEP), also called enkephalinase (EC 3.4.24.11), modulates the effects of exogenous and endogenous tachykinins in vivo, we studied the effects of aerosolized phosphoramidon, a specific NEP inhibitor, on the responses to aerosolized substance P (SP) and on the atropine-resistant response to vagus nerve stimulation (10 V, 5 ms for 20 s) in guinea pigs. SP alone (10(-7) to 10(-4) M; each concentration, 7 breaths) caused no change in total pulmonary resistance (RL, P greater than 0.5). Phosphoramidon (10(-4) M, 90 breaths) caused no change either in base-line RL (P greater than 0.5) or in the response to aerosolized acetylcholine (P greater than 0.5). However, in the presence of phosphoramidon, SP (7 breaths) produced a concentration-dependent increase in RL at concentrations greater than or equal to 10(-5) M (P less than 0.001). Phosphoramidon (10(-7) to 10(-4) M; each concentration, 90 breaths) induced a concentration-dependent potentiation of SP-induced bronchoconstriction (10(-4) M, 7 breaths; P less than 0.01). Vagus nerve stimulation (0.5-3 Hz), in the presence of atropine, induced a frequency-dependent increase in RL (P less than 0.001). Phosphoramidon potentiated the atropine-resistant responses to vagus nerve stimulation (P less than 0.001) at frequencies greater than 0.5 Hz. The tachykinin antagonist [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-substance P abolished the effects of phosphoramidon on the atropine-resistant response to vagus nerve stimulation (2 Hz, P less than 0.005). NEP-like activity in tracheal homogenates of guinea pig was inhibited by phosphoramidon with a concentration producing 50% inhibition of 5.3 +/- 0.8 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals The role of cysteinyl leukotrienes on lipopolysaccharide-induced bronchial hyperresponsiveness in guinea pigs

1996 ◽  
Vol 71 ◽  
pp. 305
Author(s):  
Takashi Uno ◽  
Hiroyuki Tanaka ◽  
Yoshizou Maeda ◽  
Akifumi Kogame ◽  
Hiroichi Nagai
Keyword(s):  
Guinea Pigs ◽  
Bronchial Hyperresponsiveness ◽  
Cysteinyl Leukotrienes

A Possible Involvement of Oxidative Lung Injury in Endotoxin-Induced Bronchial Hyperresponsiveness to Substance P in Guinea Pigs

1998 ◽  
Vol 151 (2) ◽  
pp. 245-253 ◽  
Author(s):  
Shigenori Iwamae ◽  
Hideo Tsukagoshi ◽  
Takeshi Hisada ◽  
Daisuke Uno ◽  
Masatomo Mori
Keyword(s):  
Substance P ◽  
Lung Injury ◽  
Guinea Pigs ◽  
Bronchial Hyperresponsiveness

scholarly journals Role of thromboxane A2 in the development of antigen-induced long-lasting bronchial hyperresponsiveness in actively sensitized guinea pigs.

Ensho ◽  
1994 ◽  
Vol 14 (3) ◽  
pp. 213-219
Author(s):  
Akinori Arimura ◽  
Asanuma Fujio ◽  
Atsushi Kurosawa ◽  
Hirokuni Jyoyama
Keyword(s):  
Guinea Pigs ◽  
Bronchial Hyperresponsiveness ◽  
Thromboxane A2
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