Journal of Applied Physiology, Vol 73, Issue 5 1847-1853, Copyright © 1992 by American Physiological Society
Effect of the NEP inhibitor SCH32615 on airway responses to intravenous substance P in guinea pigs
S. A. Shore, M. A. Martins and J. M. Drazen
Respiratory Biology Program, Harvard School of Public Health, Boston, Massachusetts.
We examined the effects of the selective neutral endopeptidase (NEP)
inhibitor SCH32615 on airway responses to rapid intravenous infusions of
substance P (SP) and neurokinin A (NKA) and on recovery of administered
tachykinins from arterial blood in anesthetized mechanically ventilated
guinea pigs. SCH32615, in doses that cause a marked increase in the
magnitude of bronchoconstriction induced by infused NKA, had little effect
on the changes in pulmonary conductance (GL) or dynamic compliance induced
by SP. In animals in which SCH32615 (1 mg/kg) was administered in
combination with the angiotensin-converting enzyme (ACE) inhibitor
captopril (5.7 mg/kg), the dose of SP required to decrease GL by 50% was
fourfold less than in animals that received captopril alone (P < 0.005).
SP measured in arterial blood withdrawn within 45 s of intravenous
administration of this tachykinin was not different in control and
SCH32615-treated animals, whereas captopril caused an approximately
threefold increase in SP concentrations (P < 0.005). When SCH32615 and
captopril were administered together, significantly more SP was recovered
than when captopril or SCH32615 was administered alone (P < 0.0005). Our
results are consistent with the hypothesis that both NEP and ACE contribute
to the degradation of intravenously infused SP. ACE degradation of SP is
sufficient to limit SP-induced bronchoconstriction even in the presence of
specific NEP inhibition.
