Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 9, pp 907–914 | Cite as

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

  • Nadia M. J. RupniakEmail author
  • Mary Katofiasc
  • Edward C. Burgard
  • Karl B. Thor
Original Article


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.


Tachykinin NK2 receptor Colorectal pressure Hypotension Macaque 



We thank the Wake Forest Innovations and Calvert Laboratories for their assistance.

Author contributions

KBT, ECB, and MK conceived and designed research. MK conducted experiments. MK and EB analyzed data. NMJR and KBT wrote the manuscript. All authors read and approved the manuscript.

Compliance with ethical standards

Conflict of interest

Authors NMJR, MK, KBT, and ECB are employed by, and have equity ownership in, Dignify Therapeutics LLC.

Ethical approval

All applicable international, national, and institutional guidelines for the care and use of laboratory animals were followed. All procedures performed on animals were in accordance with the ethical standards of the Wake Forest Innovations and Calvert Laboratories animal care and use committees and followed the NIH guidelines for the Care and Use of Laboratory Animals. This article does not contain any studies with human participants.


  1. Brahim JS, Thut PD (1984) Hemodynamic changes in dogs during isoflurane anesthesia. Anesth Prog 31:207–212PubMedPubMedCentralGoogle Scholar
  2. Burcher E, Shang F, Warner FJ, Du Q, Lubowski DZ, King DW, Liu L (2008) Tachykinin NK2 receptor and functional mechanisms in human colon: changes with indomethacin and in diverticular disease and ulcerative colitis. J Pharmacol Exp Therap 324:170–178CrossRefGoogle Scholar
  3. Evans TW, Dixon CM, Clarke B, Conradson TB, Barnes PJ (1988) Comparison of neurokinin A and substance P on cardiovascular and airway function in man. Br J Clin Pharmacol 25:273–275CrossRefPubMedPubMedCentralGoogle Scholar
  4. Hastrup H, Schwartz TW (1996) Septide and neurokinin A are high-affinity ligands on the NK-1 receptor: evidence from homologous versus heterologous binding analysis. FEBS Lett 399:264–266CrossRefPubMedGoogle Scholar
  5. Henderson LS, Tenero DM, Baidoo CA, Campanile AM, Harter AH, Boyle D, Danoff TM (2006) Pharmacokinetic and pharmacodynamic comparison of controlled-release carvedilol and immediate-release carvedilol at steady state in patients with hypertension. Am J Cardiol 98:17L–26LCrossRefPubMedGoogle Scholar
  6. Hikasa Y, Ohe N, Takase K, Ogasawara S (1997) Cardiopulmonary effects of sevoflurane in cats: comparison with isoflurane, halothane, and enflurane. Res Vet Sci 63:205–210CrossRefPubMedGoogle Scholar
  7. van Koeveringe GA, Vahabi B, Andersson KE, Kirschner-Herrmans R, Oelke M (2011) Detrusor underactivity: a plea for new approaches to a common bladder dysfunction. Neurourol Urodyn 30:723–728CrossRefPubMedGoogle Scholar
  8. Kullmann FA, Katofiasc M, Thor KB, Marson L (2017) 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. Naunyn Schmiedebergs Arch Pharmacol 390:163–173CrossRefPubMedGoogle Scholar
  9. Lordal M, Theodorsson E, Hellstrom PM (1997) Tachykinins influence interdigestive rhythm and contractile strength of human small intestine. Dig Dis Sci 42:1940–1949CrossRefPubMedGoogle Scholar
  10. Lordal M, Navalesi G, Theodorsson E, Maggi CA, Hellstrom PM (2001) A novel tachykinin NK2 receptor antagonist prevents motility-stimulating effects of neurokinin A in small intestine. Br J Pharmacol 134:215–223CrossRefPubMedPubMedCentralGoogle Scholar
  11. Maggi CA, Meli C (1986) Suitability of urethane anesthesia for physiopharmacological investigations in various systems. Part 2: cardiovascular system. Experientia 42:292–297CrossRefPubMedGoogle Scholar
  12. Marson L, Thor KB, Katofiasc M, Rupniak NMJ (2018) Prokinetic effects of NK2 receptor agonists on the bladder and rectum of rats with acute spinal cord transection. Eur J Pharmacol 819:261–269CrossRefPubMedGoogle Scholar
  13. Rupniak NMJ, Katofiasc M, Marson L, Thor KB (2018a) NK2 and NK1 receptor mediated effects of NKA and analogs on colon, bladder, and arterial pressure in anesthetized dogs. Naunyn Schmiedebergs Arch Pharmacol 391:299–308CrossRefPubMedGoogle Scholar
  14. Rupniak NMJ, Katofiasc M, Walz A, Thor KB, Burgard EC (2018b) [Lys5,MeLeu9,Nle10]-NKA(4–10) elicits NK2 receptor mediated micturition and defecation, and NK1 receptor mediated emesis and hypotension, in conscious dogs. J Pharmacol Exp Ther 118:248765. CrossRefGoogle Scholar
  15. Sagan S, Chassaing G, Pradier L, Lavielle S (1996) Tachykinin peptides affect differently the second messenger pathways after binding to CHO-expressed human NK-1 receptors. J Pharmacol Exp Ther 276:1039–1048PubMedGoogle Scholar
  16. Schmidt PT, Lordal M, Gazelius B, Hellstrom PM (2003) Tachykinins potently stimulate human small bowel blood flow: a laser Doppler flowmetry study in humans. Gut 52:53–56CrossRefPubMedPubMedCentralGoogle Scholar
  17. Torrens Y, Beaujouan JC, Saffroy M, Glowinski J (2000) Further evidence for the presence of "septide-sensitive" tachykinin binding sites in tissues possessing solely NK(1) tachykinin receptors. Biochem Biophys Res Commun 270:668–772CrossRefPubMedGoogle Scholar
  18. Trim CM, Braun C (2011) Anesthetic agents and complications in Vietnamese potbellied pigs: 27 cases (1999-2006). J Am Vet Med Assoc 239:114–121CrossRefPubMedGoogle Scholar
  19. Warner FJ, Comis A, Miller RC, Burcher E (1999) Characterization of the [125I]-neurokinin A binding site in the circular muscle of human colon. Br J Pharmacol 127:1105–1110CrossRefPubMedPubMedCentralGoogle Scholar
  20. Warner FJ, Miller RC, Burcher E (2003) Human tachykinin NK2 receptor: a comparative study of the colon and urinary bladder. Clin Exp Pharmacol Physiol 30:632–639CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Dignify Therapeutics LLCResearch Triangle ParkUSA

Personalised recommendations