Prokinetic effects of the neurokinin NK2 receptor agonist [Lys5,MeLeu9,Nle10]-NKA(4–10) on bladder and colorectal activity in minipigs

Abstract

The effects of the neurokinin NK2 receptor agonist [Lys5,MeLeu9,Nle10]-NKA(4–10) (LMN-NKA) on bladder and colorectal function were examined in minipigs. In anesthetized animals, subcutaneous (SC) administration of 30–100 μg/kg increased peak bladder and colorectal pressures. Increases in bladder and colorectal pressure were inhibited by a 15 min pretreatment with the NK2 receptor antagonist GR 159897 (1 mg/kg intravenously (IV)). Bladder and colorectal pressures were also increased after IV (0.3 μg/kg), intranasal (IN; 100 μg/kg) and sublingual administration (SL; 5 mg/kg). There was a nonsignificant trend for hypotension (16 or 12% decrease in mean arterial pressure) after 100 μg/kg SC and 0.3 μg/kg IV, respectively, but not after 100 μg/kg IN or 5 mg/kg SL. In conscious minipigs, 30–300 μg/kg SC caused a dose-related increase in defecation that was accompanied by emesis in 38% of subjects receiving 300 μg/kg. Urination was increased after 100 μg/kg SC but not lower or higher doses. The peak plasma exposure (Cmax) after 100 μg/kg SC was 123 ng/mL, and area under the curve (AUC) was 1790 min * ng/mL. Defecation response rates (~82%) were maintained after SC administration of LMN-NKA (30 μg/kg) given 3 times daily over 5 consecutive days. Defecation rates were higher after a single dose of 100 μg/kg IN compared with vehicle, but this did not reach significance. After 7–10 mg/kg SL, 83% of animals urinated and defecated, and none had emesis. The data support the feasibility of developing a convenient and well-tolerated route of administration of LMN-NKA for human use. Minipigs may be a suitable species for toxicology studies with LMN-NKA due to the relatively low rate of emesis in this species.