Colorectal and cardiovascular effects of [Lys⁵,MeLeu⁹,Nle¹⁰]-NKA_(4-10) in anesthetized macaques

Abstract

The effects of the tachykinin NK2 receptor agonist LMN-NKA ([Lys⁵,MeLeu⁹,Nle¹⁰]-NKA_(4-10)) on colorectal and arterial blood pressure were examined in anesthetized macaques. Intravenous (IV) administration of 1–100 μg/kg caused dose-related increases in colorectal pressure up to 120 mmHg above baseline, and area under the curve (AUC) up to 24,987 mmHg*s. This was accompanied at all doses by transient hypotension, with up to 26% reduction in mean arterial pressure (MAP) from baseline. Hypotension, but not the increase in colorectal pressure, was inhibited by a 10-min pretreatment with the NK1 receptor antagonist CP-99,994. In a pilot experiment using subcutaneous (SC) injection, a similar dose range of LMN-NKA (3–100 μg/kg) again appeared to increase colorectal pressure with a similar AUC (up to 18,546 mmHg*s) to that seen after IV injection, but lower peak amplitude (up to 49 mmHg). Unlike the effects of IV injection, hypotension was only present after the highest SC dose (100 μg/kg) in one of two animals. Pharmacokinetic analysis revealed markedly lower plasma exposures after SC compared with IV administration. Cmax was 39.6 versus 1070 ng/mL, and AUC_inf was 627 versus 2090 ng/mL*min, respectively. These findings are consistent with previous observations in anesthetized dogs and indicate that the prokinetic effects of LMN-NKA may be achieved without hypotension using a route of administration that avoids unnecessarily high plasma exposures.