Relative bronchoconstrictor activity of neurokinin A and neurokinin A fragments in guinea pigs.
We examined the effect of rapid intravenous infusion of neurokinin A (NKA) and selected COOH-terminal NKA fragments on pulmonary conductance (GL) and dynamic compliance in anesthetized mechanically ventilated guinea pigs. The rank order of the dose of peptide required to reduce GL by 50% (ED50GL) was NKA = NKA2-10 = NKA3-10 = NKA4-10 less than NKA5-10 much less than NKA6-10. The time course of bronchoconstriction induced by NKA2-10, NKA3-10, and NKA4-10 was similar to that induced by NKA, whereas NKA5-10 and NKA6-10 each had a shorter duration of action than NKA for a similar induced maximal change in GL. To determine whether degradation of these NKA fragments by neutral endopeptidase (NEP) modulates their bronchoconstrictor activity as it does for native NKA, we examined the effect of the NEP inhibitor SCH32615 on NKA3-10-, NKA5-10-, and NKA6-10-induced changes in GL. We have previously reported that the ED50GL for NKA was approximately 20-fold lower in animals pretreated with SCH32615 (1 mg/kg) than in control guinea pigs. SCH32615 caused a 16-fold decrease in ED50GL for NKA3-10 (P less than 0.001) but had no effect on airway responses to NKA5-10 or NKA6-10. The results demonstrate that the magnitude and duration of bronchoconstriction induced by potential aminopeptidase degradation products of NKA are similar to those of the native peptide. Aminopeptidases do not, therefore, have the capacity to modulate the bronchoconstriction induced by this peptide.(ABSTRACT TRUNCATED AT 250 WORDS)
Shore
S A
SA
Respiratory Biology Program, Harvard School of Public Health, Boston, Massachusetts.
Drazen
J M
JM
D000595:Amino Acid Sequence; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D007262:Infusions, Intravenous; D008297:Male; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000037:antagonists & inhibitors; D015288:Neurokinin A / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011738:Pyrilamine / Q000494:pharmacology
D016085:Bronchoconstrictor Agents; D004151:Dipeptides; D010446:Peptide Fragments; D001285:Atropine; C062344:SCH 32615; D015288:Neurokinin A; D015260:Neprilysin; D011738:Pyrilamine; D007213:Indomethacin