Substance P-induced effects in guinea pig lungs: effects of thiorphan and captopril.
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.
Drazen
J M
JM
Department of Medicine, Beth Israel Hospital, Boston, Massachusetts.
Shore
S A
SA
Gerard
N P
NP
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010477:Perfusion; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology*; D015244:Thiorphan / Q000494:pharmacology*
D013373:Substance P; D002216:Captopril; D015244:Thiorphan