title: 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.
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 (NK2receptor) 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 NK2receptor 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 NK2receptor 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.
authors.affiliation: Department of Medicine, Renal Division, University of Pittsburgh, 3500 Terrace St, Scaife A1220, Pittsburgh, PA, 15261, USA.
authors.forename: F Aura
authors.identifier: http://orcid.org/0000-0001-6625-2946
authors.initials: FA
authors.lastname: Kullmann
authors.affiliation: Dignify Therapeutics LLC, 2 Davis Drive, PO Box 13169, Research Triangle Park, NC, 27709, USA.
authors.forename: M
authors.initials: M
authors.lastname: Katofiasc
authors.affiliation: Dignify Therapeutics LLC, 2 Davis Drive, PO Box 13169, Research Triangle Park, NC, 27709, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Thor
authors.affiliation: Dignify Therapeutics LLC, 2 Davis Drive, PO Box 13169, Research Triangle Park, NC, 27709, USA. lmarson@dignifytherapeutics.com.
authors.forename: Lesley
authors.initials: L
authors.lastname: Marson
mesh_terms: D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000294:innervation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D015288:Neurokinin A / Q000031:analogs & derivatives* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011312:Pressure; D017207:Rats, Sprague-Dawley; D018041:Receptors, Neurokinin-2 / Q000187:drug effects / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation; D014563:Urodynamics / Q000187:drug effects*
chemical_list: C092990:GR 159897; D007211:Indoles; D010446:Peptide Fragments; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C083383:neurokinin A (4-10), Lys(5)-MeLeu(9)-Nle(10)-; D015288:Neurokinin A
keywords: Bladder; Colorectal pressure; Cystometry; Neurokinin 2 agonist; Spinal cord injury