Effects of TAK-637, a tachykinin receptor antagonist, on lower urinary tract function in the guinea pig

Doi, Takayuki; Izumi, Kiyotaka; Imai, Shigemitsu; Okanishi, Satoshi; Ishimaru, T.; Ikeura, Yoshinori; Natsugari, Hideaki

doi:10.1016/s0014-2999(99)00657-3

Cited by 21 publications

(11 citation statements)

References 39 publications

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Pietra

Lovati

et al. 2012

J Pharmacol Exp Ther

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The suppression of overactive bladder symptoms in patients and overactive bladder reflexes in animal models by neurokinin (NK)-1 receptor antagonists raises the possibility that these drugs target sensory neurons. This mechanism was evaluated by examining the interactions between a specific NK-1 agonist, [Sar 9 ,Met(O 2 )(11)]-substance P (Sar-Met-SP), and a potent NK-1 antagonist, netupitant (NTP), on small size (20 -30 m) dissociated L6 and S1 dorsal root ganglion (DRG) neurons from female guinea pigs. Current-clamp recording revealed that SarMet-SP (1 M) elicited membrane depolarization (average 8.05 Ϯ 1.38 mV) in 27% (18 of 65) of DRG neurons. In 74% of the remaining neurons (35 of 47) Sar-Met-SP decreased the rheobase for action potential (AP) generation and increased the response to a suprathreshold stimulus (3 times rheobase) without changing the membrane potential. Sar-Met-SP also induced changes in the action potential (AP) wave form, including 1) an increase in overshoot (average 5 mV, n ϭ 35 neurons), 2) a prolongation of AP duration (from 4.64 to 5.29 ms, n ϭ 34), and 3) a reduction in the maximal rate of AP repolarization. NTP (200 nM) reversed the Sar-Met-SP-induced changes. Ca 2ϩ imaging showed that application of Sar-Met-SP (1 M) decreased the tachyphylaxis induced by repeated application of capsaicin (0.5 M), an effect blocked by pretreatment with NTP (200 nM). These results raise the possibility that activation of NK-1 receptors in primary sensory neurons plays a role in the generation of overactive bladder and that block of NK-1 receptors in these neurons may contribute to efficacy of NK-1 antagonists in the treatment of overactive bladder symptoms.

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Section: Introductionmentioning

confidence: 99%

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

Zhang

Pietra

Lovati

et al. 2012

J Pharmacol Exp Ther

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“…A novel tachykinin NK1-receptor antagonist, TAK-637 (1), increases bladder capacity and decreases the frequency of distension-induced rhythmic bladder contractions (micturition reflex) in normal and spinal guinea pigs under urethane anesthesia (2,3). It also inhibits the bladder contractions induced by electrical stimulation of the afferent pathway, not the efferent pathway, of the spinal guinea pig pelvic nerve (4).…”

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confidence: 99%

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

Izumi

Doi

2001

Japanese Journal of Pharmacology

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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.

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“…The most consistent literature addresses the use of NK-1 receptor antagonists to reduce urinary frequency following neural injury, disease or inflammation. Clinical studies using NK-1 receptor antagonists have demonstrated a reduction in overactive bladder (OAB) symptoms (Green et al, 2006; Frenkl et al, 2010) and a reduction in hyperactive bladder reflexes induced by spinal cord injury, following cyclophosphamide-induced bladder inflammation or chemical irritation of the urinary bladder (Abdel-Gawad et al, 2001; Doi et al, 1999; 2000). It has been demonstrated that these effects reflect NK-1 receptor antagonists acting on CNS and/or PNS components of micturition reflex pathways (Lecci and Maggi, 1995; 2001; Seki et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to providing key insights into developmental maturation of voiding reflexes, these studies may also provide important information relevant to adult OAB and neurogenic voiding disorders. For example, NK-1 receptor antagonists have been used to improve bladder dysfunction in adult overactive bladder and manage neurogenic disorders of micturition (Abdel-Gawad et al, 2001; Doi et al, 1999; 2000; Frenkl et al, 2010; Green et al, 2006). In addition, studies of the development of micturition reflexes may provide insights into the management of neurogenic disorders of micturition.…”

Section: Discussionmentioning

confidence: 99%

Accelerated onset of the vesicovesical reflex in postnatal NGF-OE mice and the role of neuropeptides

Girard

Peterson

Malley

et al. 2016

Experimental Neurology

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The mechanisms underlying the postnatal maturation of micturition from a somatovesical to a vesicovesical reflex are not known but may involve neuropeptides in the lower urinary tract. A transgenic mouse model with chronic urothelial overexpression (OE) of NGF exhibited increased voiding frequency, increased number of non-voiding contractions, altered morphology and hyperinnervation of the urinary bladder by peptidergic (e.g., Sub P and CGRP) nerve fibers in the adult. In early postnatal and adult NGF-OE mice we have now examined: (1) micturition onset using filter paper void assays and open-outlet, continuous fill, conscious cystometry; (2) innervation and neurochemical coding of the suburothelial plexus of the urinary bladder using immunohistochemistry and semi-quantitative image analyses; (3) neuropeptide protein and transcript expression in urinary bladder of postnatal and adult NGF-OE mice using Q-PCR and ELISAs and (4) the effects of intravesical instillation of a neurokinin (NK)-1 receptor antagonist on bladder function in postnatal and adult NGF-OE mice using conscious cystometry. Postnatal NGF-OE mice exhibit age-dependent (R2= 0.996–0.998; p ≤ 0.01) increases in Sub and CGRP expression in the urothelium and significantly (p ≤ 0.01) increased peptidergic hyperinnervation of the suburothelial nerve plexus. By as early as P7, NGF-OE mice exhibit a vesicovesical reflex in response to intravesical instillation of saline whereas littermate WT mice require perigenital stimulation to elicit a micturition reflex until P13 when vesicovesical reflexes are first observed. Intravesical instillation of a NK-1 receptor antagonist, netupitant (0.1 μg/ml), significantly (p ≤ 0.01) increased void volume and the interval between micturition events with no effects on bladder pressure (baseline, threshold, peak) in postnatal NGF-OE mice; effects on WT mice were few. NGF-induced pleiotropic effects on neuropeptide (e.g., Sub P) expression in the urinary bladder contribute to the maturation of the micturition reflex and are excitatory to the micturition reflex in postnatal NGF-OE mice. These studies provide insight into the mechanisms that contribute to the postnatal development of the micturition reflex.

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Effects of TAK-637, a tachykinin receptor antagonist, on lower urinary tract function in the guinea pig

Cited by 21 publications

References 39 publications

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

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

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

Accelerated onset of the vesicovesical reflex in postnatal NGF-OE mice and the role of neuropeptides

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