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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. Rupniak
  • Mary Katofiasc
  • Edward C. Burgard
  • Karl B. Thor
Original Article
  • 67 Downloads

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.

Keywords

Tachykinin NK2 receptor Colorectal pressure Hypotension Macaque 

Notes

Acknowledgements

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.

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Copyright information

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

Authors and Affiliations

  1. 1.Dignify Therapeutics LLCResearch Triangle ParkUSA

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