Journal of Applied Physiology, Vol 70, Issue 2 877-881, Copyright © 1991 by American Physiological Society
Effect of neutral endopeptidase inhibition of f-Met-Leu-Phe-induced bronchoconstriction in the rabbit
M. J. Peters, K. Panaretto, L. Kemsley, A. B. Breslin and N. Berend
Department of Thoracic Medicine, Royal North Shore Hospital, University Sydney, New South Wales, Australia.
Inhalation of f-Met-Leu-Phe (FMLP) produces dose-dependent increases in
pulmonary resistance (RL) in rabbits. We hypothesized that inhibition of
neutral endopeptidase (NEP), which has high affinity for FMLP, would
augment the response to FMLP inhalation. We found the increase in RL above
baseline in response to FMLP to be reduced from 56 +/- 18 to 8 +/- 10% (P
less than 0.01) by phosphoramidon (1 mg/kg) and to 15 +/- 6% (P less than
0.02) by thiorphan (3 mg/kg). The geometric mean dose of FMLP producing a
20% rise in RL (PC20RL FMLP) was increased by phosphoramidon from 1.1 to
4.5 mg/ml (P less than 0.05). Enkephalins, which are also NEP substrates,
modulate cholinergic neurotransmission in the airway. Inhibition of the
FMLP response by phosphoramidon was reversed by coadministration of
naloxone (0.1 mg/kg); after atropine (2 mg/kg) the change in RL in response
to FMLP was reduced to 7 +/- 4% (P less than 0.01), whereas morphine (0.15
mg/kg) increased PC20RL FMLP to 5.1 mg/ml (P less than 0.05). FMLP-induced
bronchoconstriction in the rabbit is vagally mediated, and reduced
responses after NEP inhibition may reflect modulation of cholinergic
bronchoconstriction by enkephalins. Changes in airway NEP activity may
influence the activity of a wide range of its substrates, of which some are
bronchoconstrictors and others bronchodilators.
