Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Colorectal and cardiovascular effects of [Lys5,MeLeu9,Nle10]-NKA(4-10) in anesthetized macaques

Colorectal and cardiovascular effects of [Lys5,MeLeu9,Nle10]-NKA(4-10) in anesthetized macaques The effects of the tachykinin NK2 receptor agonist LMN-NKA ([Lys5,MeLeu9,Nle10]-NKA(4-10)) on colorectal and arterial blood pressure were examined in anesthetized macaques. Intravenous (IV) administration of 1–100 μg/kg caused dose-related increases in colorectal pressure up to 120 mmHg above baseline, and area under the curve (AUC) up to 24,987 mmHg*s. This was accompanied at all doses by transient hypotension, with up to 26% reduction in mean arterial pressure (MAP) from baseline. Hypotension, but not the increase in colorectal pressure, was inhibited by a 10-min pretreatment with the NK1 receptor antagonist CP-99,994. In a pilot experiment using subcutaneous (SC) injection, a similar dose range of LMN-NKA (3–100 μg/kg) again appeared to increase colorectal pressure with a similar AUC (up to 18,546 mmHg*s) to that seen after IV injection, but lower peak amplitude (up to 49 mmHg). Unlike the effects of IV injection, hypotension was only present after the highest SC dose (100 μg/kg) in one of two animals. Pharmacokinetic analysis revealed markedly lower plasma exposures after SC compared with IV administration. Cmax was 39.6 versus 1070 ng/mL, and AUCinf was 627 versus 2090 ng/mL*min, respectively. These findings are consistent with previous observations in anesthetized dogs and indicate that the prokinetic effects of LMN-NKA may be achieved without hypotension using a route of administration that avoids unnecessarily high plasma exposures. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Naunyn-Schmiedeberg's Archives of Pharmacology Springer Journals

Colorectal and cardiovascular effects of [Lys5,MeLeu9,Nle10]-NKA(4-10) in anesthetized macaques

Download PDF
8 pages

Loading next page...
 
/lp/springer_journal/colorectal-and-cardiovascular-effects-of-lys5-meleu9-nle10-nka-4-10-in-bog3idxRnx
Publisher
Springer Journals
Copyright
Copyright © 2018 by Springer-Verlag GmbH Germany, part of Springer Nature
Subject
Biomedicine; Pharmacology/Toxicology; Neurosciences
ISSN
0028-1298
eISSN
1432-1912
DOI
10.1007/s00210-018-1520-6
pmid
29858647
Publisher site
See Article on Publisher Site

Abstract

The effects of the tachykinin NK2 receptor agonist LMN-NKA ([Lys5,MeLeu9,Nle10]-NKA(4-10)) on colorectal and arterial blood pressure were examined in anesthetized macaques. Intravenous (IV) administration of 1–100 μg/kg caused dose-related increases in colorectal pressure up to 120 mmHg above baseline, and area under the curve (AUC) up to 24,987 mmHg*s. This was accompanied at all doses by transient hypotension, with up to 26% reduction in mean arterial pressure (MAP) from baseline. Hypotension, but not the increase in colorectal pressure, was inhibited by a 10-min pretreatment with the NK1 receptor antagonist CP-99,994. In a pilot experiment using subcutaneous (SC) injection, a similar dose range of LMN-NKA (3–100 μg/kg) again appeared to increase colorectal pressure with a similar AUC (up to 18,546 mmHg*s) to that seen after IV injection, but lower peak amplitude (up to 49 mmHg). Unlike the effects of IV injection, hypotension was only present after the highest SC dose (100 μg/kg) in one of two animals. Pharmacokinetic analysis revealed markedly lower plasma exposures after SC compared with IV administration. Cmax was 39.6 versus 1070 ng/mL, and AUCinf was 627 versus 2090 ng/mL*min, respectively. These findings are consistent with previous observations in anesthetized dogs and indicate that the prokinetic effects of LMN-NKA may be achieved without hypotension using a route of administration that avoids unnecessarily high plasma exposures.

Journal

Naunyn-Schmiedeberg's Archives of Pharmacology – Springer Journals

Published: Jun 1, 2018

References

  • Hemodynamic changes in dogs during isoflurane anesthesia
    Brahim, JS; Thut, PD
  • Tachykinin NK2 receptor and functional mechanisms in human colon: changes with indomethacin and in diverticular disease and ulcerative colitis
    Burcher, E; Shang, F; Warner, FJ; Du, Q; Lubowski, DZ; King, DW; Liu, L
  • Comparison of neurokinin A and substance P on cardiovascular and airway function in man
    Evans, TW; Dixon, CM; Clarke, B; Conradson, TB; Barnes, PJ
  • Septide and neurokinin A are high-affinity ligands on the NK-1 receptor: evidence from homologous versus heterologous binding analysis
    Hastrup, H; Schwartz, TW
  • Pharmacokinetic and pharmacodynamic comparison of controlled-release carvedilol and immediate-release carvedilol at steady state in patients with hypertension
    Henderson, LS; Tenero, DM; Baidoo, CA; Campanile, AM; Harter, AH; Boyle, D; Danoff, TM
  • Cardiopulmonary effects of sevoflurane in cats: comparison with isoflurane, halothane, and enflurane
    Hikasa, Y; Ohe, N; Takase, K; Ogasawara, S
  • Detrusor underactivity: a plea for new approaches to a common bladder dysfunction
    Koeveringe, GA; Vahabi, B; Andersson, KE; Kirschner-Herrmans, R; Oelke, M
  • Pharmacodynamic evaluation of Lys5,MeLeu9, Nle10-NKA(4-10) prokinetic effects on bladder and colon activity in acute spinal cord transected and spinally intact rats
    Kullmann, FA; Katofiasc, M; Thor, KB; Marson, L
  • Tachykinins influence interdigestive rhythm and contractile strength of human small intestine
    Lordal, M; Theodorsson, E; Hellstrom, PM
  • A novel tachykinin NK2 receptor antagonist prevents motility-stimulating effects of neurokinin A in small intestine
    Lordal, M; Navalesi, G; Theodorsson, E; Maggi, CA; Hellstrom, PM
  • Suitability of urethane anesthesia for physiopharmacological investigations in various systems. Part 2: cardiovascular system
    Maggi, CA; Meli, C
  • Prokinetic effects of NK2 receptor agonists on the bladder and rectum of rats with acute spinal cord transection
    Marson, L; Thor, KB; Katofiasc, M; Rupniak, NMJ
  • NK2 and NK1 receptor mediated effects of NKA and analogs on colon, bladder, and arterial pressure in anesthetized dogs
    Rupniak, NMJ; Katofiasc, M; Marson, L; Thor, KB
  • [Lys5,MeLeu9,Nle10]-NKA(4–10) elicits NK2 receptor mediated micturition and defecation, and NK1 receptor mediated emesis and hypotension, in conscious dogs
    Rupniak, NMJ; Katofiasc, M; Walz, A; Thor, KB; Burgard, EC
  • Tachykinin peptides affect differently the second messenger pathways after binding to CHO-expressed human NK-1 receptors
    Sagan, S; Chassaing, G; Pradier, L; Lavielle, S
  • Tachykinins potently stimulate human small bowel blood flow: a laser Doppler flowmetry study in humans
    Schmidt, PT; Lordal, M; Gazelius, B; Hellstrom, PM
  • Further evidence for the presence of "septide-sensitive" tachykinin binding sites in tissues possessing solely NK(1) tachykinin receptors
    Torrens, Y; Beaujouan, JC; Saffroy, M; Glowinski, J
  • Anesthetic agents and complications in Vietnamese potbellied pigs: 27 cases (1999-2006)
    Trim, CM; Braun, C
  • Characterization of the [125I]-neurokinin A binding site in the circular muscle of human colon
    Warner, FJ; Comis, A; Miller, RC; Burcher, E
  • Human tachykinin NK2 receptor: a comparative study of the colon and urinary bladder
    Warner, FJ; Miller, RC; Burcher, E