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

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Abstract
We 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 (4.6 mm, 60 breaths; 210 nmol) to inhibit ACE and acetorphan (0.3, 1 and 3 mm, 60 breaths; 9 nmol, 33 nmol and 110 nmol respectively) to inhibit NEP. We also examined the effect of the highest dose of acetorphan (110 nmol) on the response to aerosolised acetylcholine (ACh). 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. 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. Treatment with captopril (21 nmol) induced only a small, nonsignificant leftward shift of PC200 to SP (0.3 ± 0.2 log units). 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.