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

Abstract

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.

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

“…Pretreatment with the NEP24.11-inhibitor phosphoramidon, also given by the inhaled route, caused a pronounced potentiation of the increase in lung resistance induced by inhaled NKA, as well as a small but significant potentiation of airway microvascular leakage in intrapulmonary airways. We found similar effects with inhaled SP, confirming a previous study showing potentiation of the bronchoconstrictor response to SP by another NEP24.1 1-inhibitor, acetorphan (Lotvall et al, 1990b). In addition, we found that inhaled NKA was more potent than SP in increasing RL whereas inhaled SP was more potent than NKA for induction of airway microvascular leakage, which is consistent with previous studies in which these tachykinins were administered by the i.v.…”

“…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.…”

“…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).…”

The effect of peptidase inhibitors on bradykinin‐induced bronchoconstriction in guinea‐pigs in vivo

“…Both ACE and NEP inhibitors potentiate SPinduced bronchoconstriction in vitro (Sekizawa et al, 1987a,b) and in vivo (Shore et al, 1988), presumably by preventing the degradation of SP. However, when SP is given by inhalation to guinea-pigs, while its effect is potentiated by an inhaled NEP inhibitor, inhaled captopril has no effect (Lotvall et al, 1990) suggesting that NEP but not ACE is important in degrading SP delivered from the airway. For BK, captopril and phosphoramidon are equally effective which argues that inhibition of degradation of tachykinins released from sensory nerves by instilled BK cannot be the sole explanation for their effect.…”

Effects of chronic airway inflammation on the activity and enzymatic inactivation of neuropeptides in guinea pig lungs.

“…It is now well established that the physiological effects of the neuropeptides are regulated by their enzymatic degradation in the pulmonary microenvironment (7)(8)(9)(10)(11)(15)(16)(17). When SP is presented to the airway surface, its action is regulated predominantly by the activity ofNEP, while the physiological effects of VIP are regulated by NEP and a tryptic enzyme.…”