Effect of TAK-637, a Tachykinin NKrReceptor Antagonist, on Lower Urinary Tract Function in Cats

Abstract

ABSTRACT-The effect of benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H [1,4] ,7]naphthyridine-6,13-dione), a tachykinin NK1-receptor antagonist, on lower urinary tract function was investigated in cats. TAK-637 (0.1, 0.3, 1 and 3 mg /kg, i.v.) produced a dose-dependent increase in bladder capacity without any significant reduction in voiding efficiency in decerebrate cats. The maximal increase in bladder capacity was 94%. By contrast, oxybutynin at 1 and 3 mg/kg (i.v.) produced a 18% and 35% increase in bladder capacity, respectively, with a 47% and 45% reduction in voiding efficiency. TAK-637 (3 mg / kg, i.v.) did not inhibit the micturition reflex induced by electrical stimulation of the rostral brainstem near the locus coeruleus, indicating that it does not impair the well-organized micturition reflex (bladder contraction and urethral relaxation). These results suggest that TAK-637 increases bladder storage capability without inhibiting the voiding function of the lower urinary tract, presumably by inhibiting the afferent pathway of the micturition reflex, rather than the efferent pathway.

Activation of Neurokinin-1 Receptors Increases the Excitability of Guinea Pig Dorsal Root Ganglion Cells

“…Because NTP reduces voiding frequency without changing the amplitude of voiding contractions (Palea et al, 2010a), it is likely that the drug acts on the afferent rather than the efferent limb of the micturition reflex. These findings are consistent with previous reports that NK-1 antagonists decrease reflex bladder activity in anesthetized guinea pigs (Yamamoto et al, 2003) and increase bladder capacity without changing voiding efficiency in decerebrate cats (Kamo and Doi, 2001).…”

“…These agents also reduce normal bladder reflexes in guinea pig, rat, or cat (Doi et al, 1999(Doi et al, , 2000Kamo and Doi, 2001) as well as hyperactive bladder reflexes induced by spinal cord injury (Doi et al, 2000), systemic administration of L-DOPA (Ishizuka et al, 1995), or application of irritant chemicals to the bladder in the rat (Abdel-Gawad et al, 2001) or guinea pig (Doi et al, 1999(Doi et al, , 2000. Various animal studies indicate that these effects are due at least in part to actions on peripheral or central bladder sensory pathways Maggi, 1995, 2001;Seki et al, 2005).…”

Potential therapeutic targets for neurokinin-1 receptor antagonists

“…Treatment with NK1 receptor antagonists reduced both the hyperactive bladder response Downloaded by [University of Otago] at 23:13 11 October 2015 and the reactive oxygen species [73]. TAK-637 was shown to increase bladder capacity without affecting voiding efficiency in cats, presumably by inhibiting the afferent pathway through the spinal cord [74], suggesting that bladder function is not likely to be compromised by NK1 receptor antagonists.…”