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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

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Abstract

The purpose of this study was to determine feasibility of a novel therapeutic approach to drug-induced voiding after spinal cord injury (SCI) using a well-characterized, peptide, neurokinin 2 receptor (NK2 receptor) agonist, Lys5, MeLeu9, Nle10-NKA(4–10) (LMN-NKA). Cystometry and colorectal pressure measurements were performed in urethane-anesthetized, intact, and acutely spinalized female rats. Bladder pressure and voiding were monitored in response to intravenous LMN-NKA given with the bladder filled to 70% capacity. LMN-NKA (0.1–300 μg/kg) produced dose-dependent, rapid (<60 s), short-duration (<15 min) increases in bladder pressure. In intact rats, doses above 0.3–1 μg/kg induced urine release (voiding efficiency of ~70% at ≥1 μg/kg). In spinalized rats, urine release required higher doses (≥10 μg/kg) and was less efficient (30–50%). LMN-NKA (0.1–100 μg/kg) also produced dose-dependent increases in colorectal pressure. No tachyphylaxis was observed, and the responses were blocked by an NK2 receptor antagonist (GR159897, 1 mg/kg i.v.). No obvious cardiorespiratory effects were noted. These results suggest that rapid-onset, short-duration, drug-induced voiding is possible in acute spinal and intact rats with intravenous administration of an NK2 receptor agonist. Future challenges remain in regard to finding alternative routes of administration that produce clinically significant voiding, multiple times per day, in animal models of chronic SCI.

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Acknowledgements

We thank Dr. Ed Burgard for the administrative work and helpful discussions of the data. We gratefully acknowledge Integrated Laboratory Systems for their collaboration.

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Authors and Affiliations

  1. Department of Medicine, Renal Division, University of Pittsburgh, 3500 Terrace St, Scaife A1220, Pittsburgh, PA, 15261, USA

    F. Aura Kullmann

  2. Dignify Therapeutics LLC, 2 Davis Drive, PO Box 13169, Research Triangle Park, NC, 27709, USA

    M. Katofiasc, K. B. Thor & Lesley Marson

Authors
  1. F. Aura Kullmann
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  2. M. Katofiasc
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  3. K. B. Thor
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  4. Lesley Marson
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Correspondence to Lesley Marson.

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Funding

This study was funded by the NICHD of the National Institutes of Health under award number R43HD080263.

Conflict of interest

Authors LM, KBT, MK are employed by Dignify Therapeutics. Authors FAK, LM, KBT, MK have equity ownership within Dignify Therapeutics.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the Integrated Laboratory Systems animal care and use committee and followed the NIH Guidelines for the Care and Use of Laboratory Animals. This article does not contain any studies with human participants performed by any of the authors.

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Kullmann, F.A., Katofiasc, M., Thor, K.B. et al. 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-Schmiedeberg's Arch Pharmacol 390, 163–173 (2017). https://doi.org/10.1007/s00210-016-1317-4

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  • DOI: https://doi.org/10.1007/s00210-016-1317-4

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