[Lys 5 ,MeLeu 9 ,Nle 10 ]-NKA (4-10) Elicits NK2 Receptor-Mediated Micturition and Defecation, and NK1 Receptor-Mediated Emesis and Hypotension, in Conscious Dogs

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 366; no. 1; pp. 136 - 144
• Main Authors: Rupniak, Nadia M J, Katofiasc, Mary, Walz, Alexander, Thor, Karl B, Burgard, Edward C
• Format: Journal Article
• Language: English
• Published: United States 01.07.2018
• Subjects: Animals; Consciousness; Defecation - drug effects; Dogs; Hypotension - chemically induced; Neurokinin A - chemistry; Peptide Fragments - adverse effects; Peptide Fragments - pharmacokinetics; Peptide Fragments - pharmacology; Receptors, Neurokinin-1 - metabolism; Receptors, Neurokinin-2 - metabolism; Tissue Distribution; Urination - drug effects; Vomiting - chemically induced
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.118.248765

Tachykinin neurokinin 2 (NK2) receptor agonists may have potential to alleviate clinical conditions associated with bladder and gastrointestinal underactivity by stimulating contraction of visceral smooth muscle. The ability of [Lys ,MeLeu ,Nle ]-neurokinin A (LMN-NKA) to elicit micturition and defecation was examined after repeated administration in groups of 2-10 conscious dogs. Administration of 10-100 g/kg, i.v., four times daily for six consecutive days, reliably elicited micturition after ≥90% of doses and defecation after ≥50% of doses. Voiding occurred <4 minutes after dosing and was short lasting (<10 minutes). LMN-NKA was well tolerated, with emesis after ∼25% of doses at 100 g/kg, i.v. Hypotension was induced by 100 g/kg, i.v., of LMN-NKA but not by lower doses. Administration of 30-300 g/kg, s.c., twice daily for seven consecutive days, reliably elicited both urination and defecation after 88%-100% of doses, and was accompanied by a high rate of emesis (50%-100%). The onset of voiding was rapid (<7 minutes) but was more prolonged than after intravenous administration (30-60 minutes). Emesis induced by 30 or 300 g/kg, s.c., of LMN-NKA was significantly reduced (from 58% to 8% and from 96% to 54%, respectively) by a 30-minute pretreatment with the neurokinin 1 (NK1) receptor antagonist, (2 ,3 )- -(2-methoxybenzyl)-2-phenylpiperidin-3-amine (CP-99,994; 1 mg/kg, s.c.). The ability of selective NK2 receptor agonists to elicit on-demand voiding could potentially address a major unmet need in people lacking voluntary control of micturition and/or defecation. LMN-NKA unexpectedly activated NK1 receptors at doses that stimulated voiding, causing emesis and hypotension that may limit the clinical utility of nonselective NK2 receptor agonists.