Substance P-induced Bronchoconstriction in the Guinea Pig: Enhancement by Inhibitors of Neutral Metalloendopeptidase and Angiotensin-converting Enzyme

Abstract

We tested the effects of the neutral metalloendopeptidase (NEP) inhibitor, thiorphan (0.17, 0.5, and 1.7 mg i.v), and the angiotensin-converting enzyme (ACE) inhibitor, captopril (0.5, 1.7, and 5.0 mg i.v.), on the bronchoconstrictor response to rapid intravenous infusions of substance P (0.1 to 30 nmol/kg) in anesthetized, mechanically ventilated guinea pigs. The decreases in pulmonary conductance and dynamic compliance caused by substance P were greater in animals treated with either thiorphan or captopril than in control animals. Thiorphan (0.5 mg) had no effect on airway responsiveness to intravenously administered methacholine, whereas captopril (1.7 mg) caused a small increase in methacholine responsiveness. Both drugs significantly increased the recovery of immunoreactive substance P in arterial plasma after exogenous administration of the peptide. We conclude that degradation of substance P by both NEP and ACE is important for determining the magnitude of the bronchoconstriction caused by intravenous administration of this neuropeptide. These data suggest that conditions associated with diminished peptidase activity could result in enhanced responses to stimuli which cause the release of endogenous substance P.

NK1‐receptors mediate the proliferative response of human fibroblasts to tachykinins

“…This suggests that full expression of the activity of natural TKs was somehow prevented by local metabolism. Recent evidence from several groups indicates that certain peptidases such as endopeptidase 24.11 or angiotensin converting enzyme (ACE), restrict the biological activity of TKs in the mammalian periphery (Sekizawa et al, 1987a,b;Devilher et al, 1988;Shore et al, 1988;Patacchini et al, 1989;Maggi et al, 1989a). …”

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

“…Furthermore, BK is capable of releasing tachykinins from sensory nerve endings in guinea-pig perfused lung (Saria et al, 1988). 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.…”

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

“…The concentration for captopril was then chosen to give approximately the same relation to the highest concentration of acetorphan, as the relation between the dose for thiorphan and captopril in an earlier study using i.v. administration of the enzyme inhibitors (Shore et al, 1988). AChchallenged animals were treated with the highest concentration of acetorphan, in order to investigate the specificity of acetorphan for SP.…”

“…Enzymes which degrade SP seem to be important regulators of its actions (Schwartz et al, 1985;Borson et al, 1987;Stimler-Gerard, 1987;Sekizawa et al, 1987;Dusser et al, 1988;Shore et al, 1988;Sheppard & Scypinski, 1988;Umeno et al, 1989). SP is degraded in vitro by several peptidases including neutral endopeptidase (NEP) and, to a lesser degree, angiotensin-converting enzyme (ACE) (Skidgel et al, 1984).…”