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

1We have examined in guinea-pigs, in vivo, the effects of inhibition of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) on the airway response to aerosolised substance P (SP). We aerosolised captopril (4.6mM, 60 breaths; 210nmol) to inhibit ACE and acetorphan (0.3, 1 and 3mM, 60 breaths; 9nmol, 33nmol and 110nmol respectively) to inhibit NEP. We also examined the effect of the highest dose of acetorphan (110 nmol) on the response to aerosolised acetylcholine (ACh).2 Responsiveness to SP (or ACh) was measured as the change in lung resistance (RL) induced by nebulisation of increasing concentrations of SP (or ACh) before and after treatment with the inhibitor. PC200, defined as the provocative concentration inducing an increase in RL of 200% above baseline, was calculated for each challenge. 3 Administration of acetorphan before the second SP-challenge induced a dose-dependent decrease in PC200 for SP amounting to 1.8 (± 0.3) log units after treatment with 11 nmol acetorphan. Treatment with vehicle before the second SP-challenge or with 3 mM acetorphan before the second ACh-challenge had no significant effect on PC200. 4 Treatment with captopril (21 nmol) induced only a small, nonsignificant leftward shift of PC200 to SP (0.3 + 0.2 log units). 5 We conclude that a NEP-like enzyme, but not ACE, regulates the response to aerosolised SP. We suggest that the same is true for SP released endogenously from sensory nerve endings in the airway epithelial layer.

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 66%

Effects of aerosolised substance P on lung resistance in guinea‐pigs: a comparison between inhibition of neutral endopeptidase and angiotensin‐converting enzyme

Lötvall

Skoogh

Barnes

et al. 1990

“…In several studies the bronchoconstrictor response induced by inhaled SP has been shown to be potentiated by inhibition of this enzyme (Dusser et al, 1988;Lotvall et al, 1990b), and a leftward shift of a dose-response curve of up to 2 log units has been observed (Lotvall et al, 1990a). In the present study we have shown that inhibition of NEP24.11 also leads to a potentiation of the bronchoconstrictor response to inhaled NKA to a similar degree.…”

Section: Discussionsupporting

confidence: 77%

“…Recent work has shown that NEP24.11 is important in regu-lating in vivo responses to both exogenous and endogenous tachykinins (Thompson et al, 1988;Shore et al, 1988;Dusser et al, 1988;Umeno et al, 1989;Lotvall et al, 1990b;Martins et al, 1990). Thus, the bronchoconstrictor response to inhaled SP is shifted close to two log units to the left when NEP24.11 is inhibited (Lotvall et al, 1990b), and the bronchoconstrictor response to endogenous tachykinins, released by electrical vagal stimulation, is potentiated in the presence of an NEP24.11-inhibitor (Dusser et al, 1988). It has also been shown that airway microvascular leakage induced by endogenous tachykinins, is potentiated in rats pretreated with inhibitors of NEP24.11 (Umeno et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of phosphoramidon on neurokinin A‐ and substance P‐induced airflow obstruction and airway microvascular leakage in guinea‐pig

Lötvall

Elwood

Tokuyama

et al. 1991

1 The effects of the inhaled neuropeptides, neurokinin A (NKA) and substance P (SP) on lung resistance (RL) and airway microvascular permeability were studied in anaesthetized guinea-pigs.2 Single doses of inhaled NKA (3 x 10-, 1 x 10-, 3 x 10-4M; 45 breaths) and SP (1 x 10-4, 3 x 10-4, 1 X 10-3; 45 breaths) caused a dose-dependent increase in both RL and airway microvascular leakage, assessed as extravasation of the albumin marker, Evans blue dye.3 NKA at 1 x 10-4 and 3 x 10-4M resulted in a significantly higher increase in RL than SP at the same doses.4 Inhaled SP (3 x 10-4M; 45 breaths) caused significantly higher Evans blue dye extravasation in main bronchi and proximal intrapulmonary airways compared to the same dose of NKA. 5 Pretreatment with the specific inhibitor of neural endopeptidase (NEP24.11), phosphoramidon, caused an approximately 100 fold leftward shift of the RL responses to inhaled NKA and SP. 6 Phosphoramidon significantly potentiated both NKA-and SP-induced airway microvascular leakage at proximal intrapulmonary airways, but not at any other airway level. 7 Inhibition of NEP24.11 potentiate both the SP-or NKA-induced airflow obstruction to a larger extent than the induced airway microvascular leakage, suggesting that NEP24.11 is more important in the modulation of the airflow obstruction observed after these mediators.

“…This pep-tidase is a cell membrane-bound enzyme that is present in airway epithelium, glands and smooth muscle from many species including man (Llorens & Schwartz, 1981;Johnson et al, 1985). Recently inhibitors of NEP, thiorphan and phosphoramidon, have been shown to increase both the maximum responses and potency of SP and NKA on human (Black et al, 1988) and ferret (Sekizawa et al, 1987) airway smooth muscle in vitro, and on guinea-pig airways in vivo (Dusser et al, 1988). Thiorphan also potentiates the SP-induced secretion of macromolecules from the ferret trachea .…”

Section: Introductionmentioning

confidence: 99%

Receptors mediating the effects of substance P and neurokinin A on mucus secretion and smooth muscle tone of the ferret trachea: potentiation by an enkephalinase inhibitor

Webber

1989

1 The effects of substance P (SP) and neurokinin A (NKA) were examined on tracheal smooth muscle tone, mucus volume. output, lysozyme output and albumin transport across the ferret in vitro whole trachea in the presence and absence of the enkephalinase inhibitor, thiorphan.2 SP (0.001-3.pM) and NKA (0.01-10 pM) contracted the tracheal smooth muscle and increased mucus volume, lysozyme and albumin outputs into the tracheal lumen. The EC50 values for SP and NKA for all of the variables measured were significantly reduced, and all of the maximum responses were significantly enhanced by thiorphan (1O pM). 3 In the presence of thiorphan, SP (1 pM) and NKA (1OpM) produced albumin concentrations in the secreted mucus (8.9 and 7.2pg pl-1) which were greater than those in the submucosal buffer (4.2 pg pl 1).4 In the presence of thiorphan, NKA was approximately 5 times more potent than SP at contracting the tracheal smooth muscle. Conversely SP was 23, 15 and 22 times more potent than NKA at stimulating mucus volume, lysozyme and albumin outputs respectively. 5 Thus, there is neutral endopeptidase in the ferret trachea in vitro which cleaves exogenously applied SP and NKA, thereby reducing the magnitude and potency of their actions. SP and NKA contract the ferret tracheal muscle probably by an action at NK2 (or NK3)yreceptors but stimulate mucus volume output, lysozyme output and albumin transport across the tracheal wall probably by an action on NK1 receptors.