Airway responses to substance P and substance P fragments in the guinea pig.
Airway responses to rapid intravenous infusions of substance P (SP), selected carboxy terminal fragments (SP3-11, SP5-11, SP7-11, and SP9-11), and an amino terminal fragment (SP1-9) were measured in anesthetized, mechanically ventilated guinea pigs. The dose of each peptide required to decrease pulmonary conductance (GL) to 50% of baseline value was calculated in each animal. The order of ED50GL was: SP5-11 less than SP3-11 less than SP less than SP7-11. SP9-11 and SP1-9 were inactive at doses up to 1000 nmol/kg i.v. The effects of the neutral metalloendopeptidase (NEP) inhibitor, thiorphan, and the angiotensin converting enzyme (ACE) inhibitor, captopril, on airway responses to SP5-11 were examined in order to test the hypothesis that differences in degradation of SP and SP5-11 contribute to the difference in airway responsiveness to the two peptides. Thiorphan (0.5 mg/animal, i.v.) caused a significant decrease in ED50GL for SP5-11, as has been previously noted for SP. In contrast, captopril (1.7 mg/animal i.v.) had no effect on ED50GL for SP5-11, although it has a substantial effect on SP responses. These results indicate that while the carboxy terminal of SP is essential for peptide bronchoactivity, loss of amino terminal peptides (up to four residues) actually enhances bronchoconstrictor responses to the peptide. Part of this enhancement appears to result from differences in the degradation of SP and SP5-11 by ACE. The data suggest that cleavage of SP by dipeptidyl aminopeptidases could enhance its bioactivity.
Shore
S A
SA
Respiratory Biology Program, Harvard School of Public Health, Boston, MA 02115.
Drazen
J M
JM
D000595:Amino Acid Sequence; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D012137:Respiratory System / Q000187:drug effects*; D013373:Substance P / Q000494:pharmacology*
D010446:Peptide Fragments; D013373:Substance P