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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• 作者：F. Aura Kullmann ; M. Katofiasc ; K. B. Thor…
• 关键词：Spinal cord injury ; Cystometry ; Neurokinin 2 agonist ; Colorectal pressure ; Bladder
• 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：390
• 期：2
• 页码：163-173
• 全文大小：
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Pharmacology/Toxicology; Neurosciences;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-1912
• 卷排序：390

文摘

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.