Aged and Young Adult Rats Respond Similarly to Highly Selective Neurokinin 2 Receptor Agonists That Produce Urination and Defecation Without Producing Cardiovascular Side Effects.

AIMS: Underactive bladder and bowel function are common in the elderly. Neurokinin 2 receptor (NK2R) agonists induce voiding in young adult animals; however, these effects have not been sufficiently examined in aged animals. Most NK2R agonists also have activity at neurokinin 1 receptors, which produces off target effects, such as transient hypotension. Hypotension is problematic in the elderly due to increased injury risk when falling. Therefore, the aims of this study were to (1) test the ability of NK2R agonists to increase bladder and colorectal pressure without affecting blood pressure and (2) determine if daily administration of a NK2R agonist consistently induces urination and defecation in aged rats.

METHODS: Voiding cystometry and manometry were used to evaluate effects of [Arg5, MeLeu9, Nle10]-NKA(4-10) (AMN-NKA) and GR64349 on bladder and colorectal physiology, respectively, while recording blood pressure in anesthetized adult and aged F344 rats. The rapid voiding detection assay was used to test the efficacy of repeated intramuscular GR64349 dosing to induce urination and defecation in aged rats.

RESULTS: Intravenous AMN-NKA or GR64349 both increased bladder and colorectal pressure in anesthetized young adult and aged rats, but AMN-NKA produced transient hypotension. Intramuscular GR64349 produced rapid increases in bladder and colorectal pressures in aged and adult rats (10-300 µg/kg) and consistently induced defecation and urination in awake aged rats across a 2 week period of dosing (100 μg/kg/2 times/day).

CONCLUSIONS: The results show that GR64349 could be a promising therapeutic for inducing urination and defecation in the elderly without side effects such as hypotension.