Recombinant human enkephalinase (neutral endopeptidase) prevents cough induced by tachykinins in awake guinea pigs.

Kohrogi, Hirotsugu; Nadel, Jay A.; Malfroy, Bernard; Gorman, Cornelia M.; Bridenbaugh, Robert; Patton, John S.; Borson, D. B.

doi:10.1172/jci114236

Cited by 81 publications

(38 citation statements)

References 50 publications

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“…However, similar findings have been reported in the cases of awake guinea pigs that coughed during inhalation of SP and capsaicin (Kohrogi et al 1988(Kohrogi et al , 1989). An increase in cough responses to BK induced by ACE inhibitors in patients with cough seems to be related to the class of drug rather than to individual compounds, since it occured with both captopril and enalapril.…”

Section: Discussionsupporting

confidence: 82%

“…Inhibition of neutral endopeptidase is reported to potentiate cough response to SP in awake guinea pigs (Kohrogi et al 1988(Kohrogi et al , 1989 and SP is the best substrate to neutral endopeptidase (Turner et al 1985). Thus, a balance between substrate and substrate specific enzyme activity may be important for regulating cough reflex in the body, and enzyme inhibitors may be useful tools for further research toward an understanding of the most common respiratory symptom of cough.…”

Section: Discussionmentioning

confidence: 99%

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Bradykinin-Induced Cough Reflex Markedly Increases in Patients wih Cough Associated with Captopril and Enalapril.

Katsumata¹,

Sekizawa

Ujiie

et al. 1991

Tohoku J. Exp. Med.

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We studied the effects of angiotensin converting enzyme (ACE) inhibitors on cough responses to bradykinin (BK), substance P (SP) and citric acid in a double blind, random study on 10 hypertensive patients receiving ACE inhibitors. Of these patients, five had reported cough with ACE inhibitors. Cough responses to citric acid were similar between patients with and without cough, and SP up to 10-5 M did not cause cough in any of the subjects. BK caused cough at 13.4 ± 1.2 (-log M) in 5 patients with cough associated with ACE inhibitors, but it did not cause cough at concentrations up to 10-5 M in other 5 patients. One month after the withdrawal of ACE inhibitors, 5 patients were free from cough symptoms, and BK did not cause cough up to 10-5 M in these patients, except for one who coughed at 10-9 M, without changes in responses to citric acid. BK caused cough at 14.3+0.7 (-log M) although BK1_7i a major metabolite of BK by ACE, caused cough at 5.7±0.7 (-log M) in another 3 patients with cough associated with ACE inhibitor. These results suggest that impaired metabolism of BK induced by ACE inhibitors may relate to the manifestation of cough in hypertensive patients receiving ACE inhibitors.bradykinin ; ACE inhibitor ; dry cough ; hypertension Angiotensin converting enzyme (ACE) inhibitors, such as captopril and enalapril have been widely used in the treatment of systemic hypertension. However, persistent dry coughs have been often reported in hypertensive patients who have been treated with ACE inhibitors (Sesoko and

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Bradykinin-Induced Cough Reflex Markedly Increases in Patients wih Cough Associated with Captopril and Enalapril.

Katsumata¹,

Sekizawa

Ujiie

et al. 1991

Tohoku J. Exp. Med.

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“…Delayed onset of the effects of NEP blockade might re spond to the time which was necessary for production of sufficiently high levels of these mediators. The specificity 174 Tudoric/Coon/Flynn/Bosnjak Neutral Endopcptidase and Anaphylactic Bronchoconstrict ion of NEP is supported by experiments with recombinant NEP [25,26]. In conscious guinea pigs recombinant hu man NEP inhibited a cough produced by substance P and capsaicin.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of Neutral Endopeptidase Augments Anaphylactic Constriction of Guinea Pig Tracheal Smooth Muscle

Tudorić¹,

Coon²,

Flynn³

et al. 1993

Int Arch Allergy Immunol

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To determine whether tachykinins participate in antigen-induced constriction of tracheal smooth muscle, we examined the effects of a neutral endopeptidase inhibitor, phosphoramidon, the tachykinin antagonist (D-Pro⁴, D-Trp^7,9,10)-substance P(4-11), and capsaicin-induced tachykinin depletion on the responses to antigen in tracheal rings from ovalbumin-sensitized guinea pigs. In these preparations, the antigen (ovalbumin, 0.1 μg/ml) produced reproducible and durable constriction of tracheal smooth muscle. Incubation with phosphoramidon (10 min, 10 μM) prior to antigen challenge significantly augmented the magnitude of ovalbumin-induced constriction by 22% after 30 min and by 31% after 45 min. The addition of phosphoramidon at the plateau level of antigen-induced constriction produced a similar, significant increase in the magnitude of the constriction. Following incubation with tachykinin antagonist (D-Pro⁴, D-Trp^7,9,10)-substance P(4-11) (5 μM), the contractile response of the tracheal rings to the antigen was not altered. Furthermore, the addition of phosphoramidon (10 μM) did not significantly affect this contraction. Similarly, neither tachykinin antagonist nor phosphoramidon altered the ovalbumin-induced constriction of the tracheal rings from capsaicin-treated guinea pigs. Based on these findings, we hypothesize that tachykinins or similar broncho-constricting neutral endopeptidase substrates were released from tachykinin-containing nerve endings during immediate hypersensitivity reaction in airways, manifesting a modest and delayed constrictive effect. Following alteration of endopeptidase activity, these substances could modulate the anaphylactic constriction of the airway smooth muscle.

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“…Similarly, the suppression of NEP activity potentiates the increase in total pulmonary resistance caused by tachykinins in guineapigs [36] and humans [37,38]. In guinea-pigs, bronchoconstriction in response to inhaled SP is accompanied by cough, an effect which is also increased by NEP inhibition and decreased by pretreatment with aerosolized rNEP [39].…”

Section: Effect Of Nep Inhibition On Airway Responses To Tachykinins mentioning

confidence: 95%

Regulation of airway neurogenic inflammation by neutral endopeptidase

Maria¹,

Bellofiore²,

Geppetti³

1998

Eur Respir J

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Airway neurogenic inflammation is caused by tachykinins released from peripheral nerve endings of sensory neurons within the airways, and is characterized by plasma protein extravasation, airway smooth muscle contraction and increased secretion of mucus. Tachykinins are degraded and inactivated by neutral endopeptidase (NEP), a membrane-bound metallopeptidase, which is located mainly at the surface of airway epithelial cells, but is also present in airway smooth muscle cells, submucosal gland cells and fibroblasts. The key role of NEP in limiting and regulating the neurogenic inflammation provoked by different stimuli has been demonstrated in a large series of studies published in recent years. It has also been shown that a variety of factors, which are relevant for airway diseases, including viral infections, allergen exposure, inhalation of cigarette smoke and other respiratory irritants, is able to reduce NEP activity, thus enhancing the effects of tachykinins within the airways. On the basis of these observations, the reduction of neutral endopeptidase activity may be regarded as a factor that switches neurogenic airway responses from their physiological and protective functions to a detrimental role that increases and perpetuates airway inflammation. However, further studies are needed to assess the role of neutral endopeptidase down regulation in the pathogenesis of asthma and other inflammatory airway diseases.

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Recombinant human enkephalinase (neutral endopeptidase) prevents cough induced by tachykinins in awake guinea pigs.

Cited by 81 publications

References 50 publications

Bradykinin-Induced Cough Reflex Markedly Increases in Patients wih Cough Associated with Captopril and Enalapril.

Bradykinin-Induced Cough Reflex Markedly Increases in Patients wih Cough Associated with Captopril and Enalapril.

Inhibition of Neutral Endopeptidase Augments Anaphylactic Constriction of Guinea Pig Tracheal Smooth Muscle

Regulation of airway neurogenic inflammation by neutral endopeptidase

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