Effect of KW-7158, a putative afferent nerve inhibitor, on bladder and vesico-vascular reflexes in rats

Lu, Shing-Hwa; Yamagata, Tsuyoshi; Atsuki, Kaoru; Sun, Lushen; Smith, Christopher P.; Yoshimura, Naoki; Chancellor, Michael B.; Groat, William C. de

doi:10.1016/s0006-8993(02)02828-7

Cited by 22 publications

(20 citation statements)

References 20 publications

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“…Conversely, KW-7158, a K + channel opener that activates a 4-AP sensitive K + current, antagonizes the increase in firing triggered by substance P in phasic, capsaicin-responsive DRG neurons (Sculptoreanu et al, 2004). Systemic administration of KW-7158 also reduces the bladder hyperactivity induced by chemical irritation of the bladder (Lu et al, 2002).…”

Section: Introductionmentioning

confidence: 97%

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Sculptoreanu

Groat

2007

Experimental Neurology

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Neurokinins released by capsaicin-responsive (C-R) dorsal root ganglia neurons (DRG) may control firing in these neurons by an autofeedback mechanism. Here we used patch clamp techniques to examine the effects of neurokinins on firing properties of dissociated DRG neurons of male rats. In C-R neurons that generated only a few action potentials (APs, termed phasic) in response to long depolarizing current pulses (600 ms), substance P (SP, 0.5 μM) lowered the AP threshold by 11.0 ±0.3 mV and increased firing from 1.1±0.7 APs to 5.2±0.6 APs. In C-R tonic neurons that fire multiple APs, SP elicited smaller changes in AP threshold (6.0±0.1 mV reduction) and the number of APs (11±1 vs. 9±1 in control). The effects of SP were similar to the effect of heteropodatoxin II (0.05 μM) or low concentrations of 4-aminopyridine (50 μM) that block A-type K + currents. A selective NK 2 agonist, [βAla 8 ]-neurokinin A (4-10) (0.5 μM), mimicked the effects of SP. The effects of SP in C-R phasic neurons were fully reversed by an NK 2 receptor antagonist (MEN10376, 0.5 μM) but only partially by a protein kinase C (PKC) inhibitor (bisindolylmaleimide, 0.5 μM). An NK 3 selective agonist ([MePhe 7 ]-neurokinin B, 0.5 μM), an NK 1 selective agonist ([Sar 9 , Met 11 ]-substance P, 0.5 μM) or activation of PKC with phorbol 12, 13-dibutyrate (0.5 μM) did not change firing. Our data suggest that the excitability of C-R phasic afferent neurons is increased by activation of NK 2 receptors and intracellular signaling mediated only in part by PKC.

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Section: Introductionmentioning

confidence: 97%

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Sculptoreanu

Groat

2007

Experimental Neurology

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“…The A-type voltage-gated K ϩ channel activator KW-7158 increases bladder capacity via a potentiation of neuronal A-type currents in bladder neurons. This dampens neuronal firing and reduces bladder stimulation (22,31). Activation of UBSM ATP-sensitive K ϩ channels hyperpolarizes the resting UBSM membrane potential and reduces the action potential frequency, resulting in a decreased contractility (3,21,30) and an increased bladder capacity (27).…”

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confidence: 99%

Small-conductance, Ca²⁺-activated K⁺ channel 2 is the key functional component of SK channels in mouse urinary bladder

Thorneloe¹,

Knorn²,

Doetsch³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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-activated K ϩ (SK) channels play an important role in regulating the frequency and in shaping urinary bladder smooth muscle (UBSM) action potentials, thereby modulating contractility. Here we investigated a role for the SK2 member of the SK family (SK1-3) utilizing: 1) mice expressing ␤-galactosidase (␤-gal) under the direction of the SK2 promoter (SK2 ␤-gal mice) to localize SK2 expression and 2) mice lacking SK2 gene expression (SK2 Ϫ/Ϫ mice) to assess SK2 function. In SK2 ␤-gal mice, UBSM staining was observed, but staining was undetected in the urothelium. Consistent with this, urothelial SK2 mRNA was determined to be 4% of that in UBSM. Spontaneous phasic contractions in wild-type (SK2 ϩ/ϩ ) UBSM strips were potentiated (259% of control) by the selective SK channel blocker apamin (EC 50 ϭ 0.16 nM), whereas phasic contractions of SK2 Ϫ/Ϫ strips were unaffected. Nerve-mediated contractions of SK2 ϩ/ϩ UBSM strips were also increased by apamin, an effect absent in SK2 Ϫ/Ϫ strips. Apamin increased the sensitivity of SK2 ϩ/ϩ UBSM strips to electrical field stimulation, since pretreatment with apamin decreased the frequency required to reach a 50% maximal contraction (vehicle, 21 Ϯ 4 Hz, n ϭ 6; apamin, 12 Ϯ 2 Hz, n ϭ 7; P Ͻ 0.05). In contrast, the sensitivity of SK2 Ϫ/Ϫ UBSM strips was unaffected by apamin. Here we provide novel insight into the molecular basis of SK channels in the urinary bladder, demonstrating that the SK2 gene is expressed in the bladder and that it is essential for the ability of SK channels to regulate UBSM contractility.bladder; contractility; small-conductance calcium-activated potassium channel; apamin THE COORDINATION OF NEURONAL and smooth muscle electrical activity is critical to the maintenance of proper urinary bladder function. Micturition occurs through the initiation of action potentials within the parasympathetic nerves leading to the bladder. These neuronal action potentials on reaching efferent terminals evoke the release of the excitatory neurotransmitters, acetylcholine and ATP. Acetylcholine and ATP bind to muscarinic (M 2 , M 3 ) and purinergic (P 2X1 ) receptors, respectively, located in the urinary bladder smooth muscle (UBSM) membrane. These transmitters contract the bladder via a coordinated potentiation of UBSM action potentials, which occur "spontaneously" during bladder filling functioning to maintain an appropriate basal bladder tone (10).Overactive bladder, a major underlying cause of urinary incontinence, is frequently caused by alterations in neuronal and/or UBSM electrical activity. Currently, the main therapy used to treat overactive bladder is muscarinic receptor antagonists that function to reduce the coupling of excitatory acetylcholine to UBSM muscarinic receptors. These agents are somewhat effective but have significant side effects, such as dry mouth, and in some cases can lead to incomplete urine voiding during micturition. Therefore, the identification of novel targets to be used for the development of better therapies for overactive bladder and urinar...

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“…Recent studies in our laboratory (Lu et al, 2002) revealed that a new compound, 3,5,[1]benzothiepin-9-yl)propanamide], can depress the excitability of afferent pathways from the urinary bladder and reduce bladder overactivity induced by chemical irritation of the urinary tract with xylene, an agent that activates capsaicin-sensitive, C-fiber afferent nerves. KW-7158 also reduced the rise in blood pressure induced by bladder distension (i.e., the vesico-vascular reflex) in urethane anesthetized rats without altering basal blood pressure (Lu et al, 2002).…”

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confidence: 99%

KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] Enhances A-Type K⁺ Currents in Neurons of the Dorsal Root Ganglion of the Adult Rat

Sculptoreanu

Yoshimura²,

Groat³

2004

J Pharmacol Exp Ther

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Recent studies revealed that a new compound, KW-7158 [(2S)-(ϩ)-3,3,3-trifluoro-2-hydroxy-2-methyl-N- (5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide], can depress the excitability of afferent pathways from the urinary bladder and reduce bladder overactivity induced by chemical irritation of the urinary tract with xylene, an agent that sensitizes capsaicin-sensitive, C-fiber afferent nerves. In the present experiments, we examined the mechanisms that might underlie the depressant effect of KW-7158 on primary afferent neurons by studying the actions of the compound on ion channels and firing in dissociated dorsal root ganglion (DRG) cells from adult rats using whole cell patch-clamp techniques. KW-7158 increased transient, A-type K ϩ currents at concentrations ranging from 50 nM to 1 M (20 -50% increases). Similar effects were seen in fast blue identified bladder afferent neurons. Low concentrations of KW-7158 shortened the action potential duration, produced a 5-to 10-mV hyperpolarization, and inhibited repetitive firing induced by either 4-AP (50 M) or substance P (0.5 M) in phasic firing DRG neurons. Above 1 M, KW-7158 elicited a smaller enhancement of A-type K ϩ currents and in high concentrations inhibited the currents. Tetraethylammonium (5-60 mM) and verapamil (50 M), which block noninactivating K ϩ currents, did not prevent the facilitatory effects of KW-7158. High concentrations of 4-AP (5 mM) inhibited A-type K ϩ currents and prevented the facilitatory effect of KW-7158 on the remaining currents. These data suggest that KW-7158 enhances A-type K ϩ currents in DRG neurons. Because A-type K ϩ channels regulate afferent neuron excitability and firing properties, KW-7158 is a promising new compound for treatment of hyper-reflexic bladder conditions.

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Effect of KW-7158, a putative afferent nerve inhibitor, on bladder and vesico-vascular reflexes in rats

Cited by 22 publications

References 20 publications

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Small-conductance, Ca²⁺-activated K⁺ channel 2 is the key functional component of SK channels in mouse urinary bladder

KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] Enhances A-Type K⁺ Currents in Neurons of the Dorsal Root Ganglion of the Adult Rat

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Effect of KW-7158, a putative afferent nerve inhibitor, on bladder and vesico-vascular reflexes in rats

Cited by 22 publications

References 20 publications

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Small-conductance, Ca2+-activated K+ channel 2 is the key functional component of SK channels in mouse urinary bladder

KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] Enhances A-Type K+ Currents in Neurons of the Dorsal Root Ganglion of the Adult Rat

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Small-conductance, Ca²⁺-activated K⁺ channel 2 is the key functional component of SK channels in mouse urinary bladder

KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] Enhances A-Type K⁺ Currents in Neurons of the Dorsal Root Ganglion of the Adult Rat