[Lys5,MeLeu9,Nle10]-NKA(4-10) Elicits NK2 Receptor-Mediated Micturition and Defecation, and NK1 Receptor-Mediated Emesis and Hypotension, in Conscious Dogs

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 [Lys⁵,MeLeu⁹,Nle¹⁰]-neurokinin A_(4-10) (LMN-NKA) to elicit micturition and defecation was examined after repeated administration in groups of 2-10 conscious dogs. Administration of 10-100 μg/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 μg/kg, i.v. Hypotension was induced by 100 μg/kg, i.v., of LMN-NKA but not by lower doses. Administration of 30-300 μg/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 μg/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, (2S,3S)-N-(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.