ORIGINAL ARTICLE
Colorectal and cardiovascular effects of [Lys
5
,MeLeu
9
,Nle
10
]-NKA
(4-10)
in anesthetized macaques
Nadia M. J. Rupniak
1
&
Mary Katofiasc
1
&
Edward C. Burgard
1
&
Karl B. Thor
1
Received: 5 April 2018 /Accepted: 25 May 2018 /Published online: 1 June 2018
#
Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
The effects of the tachykinin NK2 receptor agonist LMN-NKA ([Lys
5
,MeLeu
9
,Nle
10
]-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.
Keywords Tachykinin NK2 receptor
.
Colorectal pressure
.
Hypotension
.
Macaque
Introduction
Loss of voluntary control of micturition and defecation ac-
companies many neurological conditions, such as injury to
the spinal cord, and often causes urinary and fecal retention
and incontinence. There are currently no effective therapies to
facilitate urination or defecation, and improved clinical man-
agement of these conditions remains an important area of un-
metneed(vanKoeveringeetal.2011). Direct contraction of
the bladder and intestinal smooth muscle using short-acting,
peptide, tachykinin NK2 receptor (NK2R) agonists may pro-
vide a novel therapeutic approach to efficiently empty the
bladder and bowel Bon demand^ in such individuals. The
ability of NK2R agonists to contract isolated bladder and co-
lon preparations via activation of NK2 receptors on visceral
smooth muscle from various species, including humans, is
well established (Warner et al. 1999;Warneretal.2003;
Burcher et al. 2008) but has only recently been examined in
vivo. The prototype NK2R agonist, LMN-NKA
([Lys
5
,MeLeu
9
,Nle
10
]-NKA
(4-10)
), increased colorectal and
bladder pressure via activation of NK2 receptors and elicited
voiding of urine following intravenous (IV) administration in
anesthetized rats and dogs (Kullmann et al. 2017;Marsonet
al. 2018; Rupniak et al. 2018a). The increase in bladder and
colorectal pressure was seen across a similar dose range in
both species (1–100 μg/kg in rats; 0.1–30 μg/kg in dogs)
and was inhibited by pretreatment with the selective NK2R
antagonist GR 159897 (Kullmann et al. 2017; Rupniak et al.
2018a).
Whereas LMN-NKA was generally well tolerated in rats,
apart from transient hypotension that was seen only at the
highest dose (100 μg/kg IV; Marson et al. 2018), dogs were
surprisingly sensitive to the hypotension, which was apparent
even after the lowest IV doses that exhibited prokinetic activ-
ity (Rupniak et al. 2018a). The sensitivity of dogs to hypoten-
sion at such low doses of LMN-NKA was also unexpected
based on studies in humans in which the endogenous peptide,
* Nadia M. J. Rupniak
nrupniak@dignifytherapeutics.com
1
Dignify Therapeutics LLC, 2 Davis Drive, P.O. Box 13169, Research
Triangle Park, NC 27709, USA
Naunyn-Schmiedeberg's Archives of Pharmacology (2018) 391:907–914
https://doi.org/10.1007/s00210-018-1520-6
@Phil_Robichaud
@deepthiw
@JoseServera