Bronchoconstrictor activities of NP gamma and NPK in anaesthetized guinea-pigs: effect on NEP inhibition.
The effects of rapid intravenous infusions of gamma-preprotachykinin-(72-92)-peptide amide (neuropeptide gamma) or beta-preprotachykinin-(72-107)-peptide amide (neuropeptide K), two N-terminally extended forms of neurokinin A (NKA), on pulmonary mechanics were examined in anaesthetized mechanically ventilated guinea-pigs. Neuropeptide gamma (NP gamma) and neuropeptide K (NPK) each caused dose-related decreases in pulmonary conductance (GL). The rank order of potency as bronchoconstrictors for the three peptides was NPK > NP gamma > NKA. Pretreatment of guinea-pigs with the neutral endopeptidase (NEP) inhibitor SCH32615 (1 mg/kg iv) decreased the doses of NP gamma and NKA required to cause a 50% decrease in GL by 3.8- and 4.9-fold respectively, but did not significantly alter NPK-induced bronchoconstriction. In animals without SCH32615, the time course of bronchoconstriction was similar for NKA and NP gamma, but NPK caused significantly more prolonged changes in GL. SCH32615 did not alter the time course of bronchoconstriction induced by NKA or NPK, but prolonged the changes in GL induced by NP gamma. The results indicate that post-translational processing of gamma- and beta-preprotachykinin mRNAs to yield NP gamma and NPK instead of NKA results in an enhanced duration of effect and an increase in bronchoconstrictor potency.
Shore
S A
SA
Respiratory Biology Program, Harvard School of Public Health, Boston, Massachusetts 02115.
Sharpless
C
C
Drazen
J M
JM
D000595:Amino Acid Sequence; D000777:Anesthetics; D000818:Animals; D016085:Bronchoconstrictor Agents / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D015288:Neurokinin A / Q000494:pharmacology; D009479:Neuropeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D012121:Respiration, Artificial; D015320:Tachykinins / Q000494:pharmacology*
D000777:Anesthetics; D016085:Bronchoconstrictor Agents; D004151:Dipeptides; D009479:Neuropeptides; D010446:Peptide Fragments; D015320:Tachykinins; C045206:neuropeptide K; C059905:tachykinin neuropeptide gamma; C062344:SCH 32615; D015288:Neurokinin A; D015260:Neprilysin