NK2 and NK1 receptor-mediated effects of NKA and analogs on colon, bladder, and arterial pressure in anesthetized dogs

Abstract

Tachykinin NK2 receptor (NK2R) agonists have potential to alleviate clinical conditions associated with bladder and gastrointestinal under activity. The effects of agonists with differing selectivity for NK2R over NK1Rs on colorectal, bladder, and cardiovascular function were examined in anesthetized dogs. Intravenous (IV) administration of NKA, LMN-NKA ([Lys⁵,MeLeu⁹,Nle¹⁰]-NKA_(4–10)), and [β-Ala⁸]-NKA_(4–10) caused a dose-related increase in colorectal pressure (up to 98 mmHg) that was blocked by pretreatment with the NK2R antagonist GR 159897 (1 mg/kg), and hypotension (decrease in mean arterial pressure of ~40 mmHg) that was blocked by the NK1R antagonist CP-99,994 (1 mg/kg). Despite the greater in vitro selectivity of LMN-NKA and [β-Ala⁸]-NKA_(4–10) for NK2R over NK1Rs compared with NKA, all 3 agonists increased colorectal pressure and caused hypotension within a similar dose range when administered as a bolus (0.1–300 μg/kg IV), or even as a slow IV infusion over 5 min (NKA; 0.02–0.6 μg/kg/min). In contrast, subcutaneous (SC) administration of LMN-NKA (3–10 μg/kg) increased colorectal pressure (up to 50 mmHg) and elicited micturition (≧ 85% voiding efficiency) without causing hypotension. NK2R agonists can produce rapid-onset, short-duration, colorectal contractions, and efficient voiding of urine without hypotension after SC administration, indicating that routes of administration that avoid the high plasma concentrations associated with IV dosing improve the separation between desired and unwanted pharmacodynamic effects. The potent hypotensive effect of NKA in dogs was unexpected based on published studies in humans in which IV infusion of NKA did not affect blood pressure at doses that increased gastrointestinal motility.