Differential effects of phosphoramidon and captopril on NK1 receptor-mediated plasma extravasation in the rat trachea

James J. Brokaw, Gary White

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

We sought to confirm the identity of the tachykinin receptor subtype that mediates plasma extravasation in the rat trachea, and assess the respective contributions of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) in regulating this tachykinin-induced response. To achieve these aims, we determined the relative potencies of several natural tachykinins and receptor-selective synthetic agonists, both before and after inhibiting NEP with phosphoramidon and ACE with captopril. We also determined the effects of these peptidase inhibitors, and the NK-1 receptor antagonist L-703,606, on the plasma extravasation produced by capsaicin, which releases tachykinins endogenously from sensory nerve endings. We found that the rank order of potency for producing plasma extravasation in the rat trachea was NK-1 receptor agonist ([Sar9, Met(O2)11] SP)>substance P>neurokinin A> neurokinin B. The NK-2 ([Nle10]NKA (4-10)) and NK-3 ([MePhe7]NKB) receptor agonists were without effect. We observed no change in the relative potencies of these peptides after giving rats phosphoramidon or captopril, which suggests that the different peptide potencies are not simply the consequence of different rates of enzymatic degradation. Nevertheless, the responses to substance P and neurokinin A were clearly potentiated in rats given phosphoramidon, indicating that NEP effectively degrades tachykinins in vivo. No significant potentiation was evident for any peptide in rats given captopril. Similarly, the plasma extravasation produced by capsaicin was potentiated in rats given phosphoramidon, but not in those given captopril. Pretreating rats with L-703,606 abolished the response to capsaicin. We conclude from these observations that NK-1 receptors mediate tachykinin-induced plasma extravasation in the rat trachea, and that NEP regulates this response with little or no contribution from ACE.

Original languageEnglish
Pages (from-to)34-39
Number of pages6
JournalAgents and Actions
Volume42
Issue number1-2
DOIs
StatePublished - Aug 1994

Fingerprint

Captopril
Trachea
Rats
Plasmas
Tachykinins
Neprilysin
Neurokinin-1 Receptors
L 703606
Capsaicin
Peptidyl-Dipeptidase A
Tachykinin Receptors
Neurokinin A
Substance P
Peptides
Neurokinin B
phosphoramidon
Sensory Receptor Cells
Protease Inhibitors
Degradation

Keywords

  • Angiotensin-converting enzyme
  • Neutral endopeptidase
  • Tachykinins
  • Trachea
  • Vascular permeability

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology (medical)

Cite this

Differential effects of phosphoramidon and captopril on NK1 receptor-mediated plasma extravasation in the rat trachea. / Brokaw, James J.; White, Gary.

In: Agents and Actions, Vol. 42, No. 1-2, 08.1994, p. 34-39.

Research output: Contribution to journalArticle

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abstract = "We sought to confirm the identity of the tachykinin receptor subtype that mediates plasma extravasation in the rat trachea, and assess the respective contributions of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) in regulating this tachykinin-induced response. To achieve these aims, we determined the relative potencies of several natural tachykinins and receptor-selective synthetic agonists, both before and after inhibiting NEP with phosphoramidon and ACE with captopril. We also determined the effects of these peptidase inhibitors, and the NK-1 receptor antagonist L-703,606, on the plasma extravasation produced by capsaicin, which releases tachykinins endogenously from sensory nerve endings. We found that the rank order of potency for producing plasma extravasation in the rat trachea was NK-1 receptor agonist ([Sar9, Met(O2)11] SP)>substance P>neurokinin A> neurokinin B. The NK-2 ([Nle10]NKA (4-10)) and NK-3 ([MePhe7]NKB) receptor agonists were without effect. We observed no change in the relative potencies of these peptides after giving rats phosphoramidon or captopril, which suggests that the different peptide potencies are not simply the consequence of different rates of enzymatic degradation. Nevertheless, the responses to substance P and neurokinin A were clearly potentiated in rats given phosphoramidon, indicating that NEP effectively degrades tachykinins in vivo. No significant potentiation was evident for any peptide in rats given captopril. Similarly, the plasma extravasation produced by capsaicin was potentiated in rats given phosphoramidon, but not in those given captopril. Pretreating rats with L-703,606 abolished the response to capsaicin. We conclude from these observations that NK-1 receptors mediate tachykinin-induced plasma extravasation in the rat trachea, and that NEP regulates this response with little or no contribution from ACE.",
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