Journal of Applied Physiology, Vol 66, Issue 3 1364-1372, Copyright © 1989 by American Physiological Society
Substance P-induced effects in guinea pig lungs: effects of thiorphan and captopril
J. M. Drazen, S. A. Shore and N. P. Gerard
Department of Medicine, Beth Israel Hospital, Boston, Massachusetts.
The effects of the neutral metalloendopeptidase inhibitor, thiorphan, and
the angiotensin-converting enzyme inhibitor, captopril, on the changes in
airway opening pressure (PaO), pulmonary arterial pressure (Ppa), and
weight induced by intravascular administration of substance P were examined
in isolated perfused and ventilated guinea pig lungs. Administration of 1
nmol substance P without enzyme inhibitors resulted in a significant (P
less than 0.01) increase in the peak PaO during ventilation from 12.4 +/-
0.5 to 22.4 +/- 2.2 cmH2O; there were small statistically insignificant
increases in Ppa. The changes in PaO peaked approximately 30 s after
peptide infusion and returned to preinfusion values by 5 min. In the
presence of combined thiorphan (5.6 microM) and captopril (7.7 microM) the
magnitude of the Pao response at 30 s (41.5 +/- 3.8 cmH2O) and at 5 min
(40.0 +/- 3.6 cmH2O) after peptide infusion was significantly greater than
in control lungs (P less than 0.05). The effects of substance P on PaO in
the presence of the various inhibitors were not related to amount of
peptide recovered in the lung effluent. Reverse-phase high-performance
liquid chromatographic analysis of [3H]Pro2,4 substance P perfused through
the lungs demonstrated that the major products were consistent with intact
substance P, substance P 1-4, and smaller peptides; only minor amounts of
products consistent with substance P 1-7, 1-9, or 3-11 were identified.
These data support our previous findings showing that the physiological
effects of intravascular substance P are limited by peptide degradation;
the latter process, once begun, proceeds rapidly to nearly complete peptide
degradation.
