Kinetics of peptide‐induced release of inflammatory mediators by the urinary bladder

Saban, Marcia R.; Saban, Ricardo; Bjorling, Dale E.

doi:10.1046/j.1464-410x.1997.00415.x

Cited by 28 publications

(16 citation statements)

References 6 publications

(7 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SP and neurokinin A released from DRG neurons act on receptors expressed in afferent neurons and afferent nerve terminals in the periphery and activate phospholipase C (Saban et al, 1997;Ruggieri, 1998). Disruption of the preprotachychynin gene, which codes for SP, leads to an impaired response to chemical irritation of the urinary tract in mice (Kiss et al, 2001).…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…Since DRG neurons express functional neurokinin receptor types 1, 2 and 3 (Brechenmacher et al, 1998,Sculptoreanu andde Groat, 2003), it has been proposed that neurokinins may act in an autofeedback manner to regulate afferent terminal excitability (Morrison et al, 1999;Sculptoreanu and de Groat, 2003;Sculptoreanu et al, 2004). Saban et al, (1997) and Morrison et al, (1999) have presented evidence for such an action at afferent terminals in the urinary bladder of the rat. Substance P has also been implicated as a neurotransmitter mediating bladder hyperactivity induced by chemical irritation (Maggi, 1997b).…”

Section: Introductionmentioning

confidence: 99%

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Sculptoreanu

Groat

2007

Experimental Neurology

View full text Add to dashboard Cite

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.

show abstract

“…Tachykinins have been reported to stimulate the release of prostanoids from the urinary bladder [13,14]. Prostanoids are important modulators of bladder function and micturition, and are potent spasmogens of the urinary bladder [15,16].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of neurokinin A‐ and substance P‐induced contractions in rat detrusor smooth muscle in vitro

2004

View full text Add to dashboard Cite

(1 m mol/L), peptidase inhibitors (captopril, thiorphan and bestatin; 1 m mol/L each) or piroxicam (10 m mol/L). The rank order of potency of agonists was neurokinin A > substance P > carbachol. Contractile responses to neurokinin A and substance P, like the contractile responses to carbachol, were abolished in a nominally Ca 2+-free medium and significantly reduced by nifedipine (1 m mol/L). SKF-96365 (60 m mol/L), an inhibitor of receptor-mediated Ca 2+ entry, abolished the nifedipine-resistant response to substance P and carbachol, and significantly attenuated the response to neurokinin A. Depleting intracellular Ca 2+ stores with thapsigargin (1 m mol/L) significantly attenuated neurokinin A-induced contractions but had no effect on substance P-or carbachol-induced contractions. The Rho-kinase inhibitor, Y-27632 (10 m mol/L), significantly reduced both phasic and tonic components of the contractile responses to neurokinin A, substance P and carbachol. CONCLUSIONThe contractile responses induced by tachykinins in rat urinary bladder smooth muscle strips involve a direct action on smooth muscle and are not modulated by peptidases or prostanoids. Neurokinin A and substance P, like carbachol-induced contractions, depend on extracellular Ca 2+ influx largely through voltage-operated and partly through receptor-operated Ca 2+ channels. Intracellular Ca 2+ release contributes to the contractile response to neurokinin A but appears to have no involvement in substance P-and carbacholinduced contractions. Rho-kinase activation contributes to contractions induced by substance P, neurokinin A and carbachol.

show abstract

Kinetics of peptide‐induced release of inflammatory mediators by the urinary bladder

Cited by 28 publications

References 6 publications

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

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

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Mechanisms of neurokinin A‐ and substance P‐induced contractions in rat detrusor smooth muscle in vitro

Contact Info

Product

Resources

About

Kinetics of peptide‐induced release of inflammatory mediators by the urinary bladder

Cited by 28 publications

References 6 publications

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

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

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Mechanisms of neurokinin A‐ and substance P‐induced contractions in rat detrusor smooth muscle in vitro

Contact Info

Product

Resources

About

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

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