Abstract
Tachykinin NK2 receptor agonists may have potential to alleviate clinical conditions associated with bladder and gastrointestinal under-activity by stimulating contraction of visceral smooth muscle. The ability of [Lys5,MeLeu9,Nle10]-NKA(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., 4 times daily for 6 consecutive days, reliably elicited micturition after >90% of doses and defecation after >50% of doses. Voiding occurred <4 min after dosing and was short-lasting (<10 min). 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 7 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 min) but was more prolonged than after IV administration (30-60 min). 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 min pretreatment with the NK1 receptor antagonist, 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.
- The American Society for Pharmacology and Experimental Therapeutics