[Lys5,MeLeu9,Nle10]-NKA(4–10) Elicits NK2 Receptor–Mediated Micturition and Defecation, and NK1 Receptor–Mediated Emesis and Hypotension, in Conscious Dogs

Rupniak, N. M. J.; Katofiasc, Mary; Walz, Alexander; Thor, Karl B.; Burgard, Edward C.

doi:10.1124/jpet.118.248765

Cited by 12 publications

(7 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[ 59 – 61 ] NK-2R agonists can produce rapid-onset and short-duration, dose-dependent elevations in bladder pressure. [ 62 – 64 ] In conscious, spinal intact dogs, NK-2R agonists elicit efficient voiding within minutes of the administration. [ 64 ] This effect is also observed in anesthetized, acute SCI rats.…”

Section: P Lasticity Of N Eurotransmitte...mentioning

confidence: 99%

“…[ 62 – 64 ] In conscious, spinal intact dogs, NK-2R agonists elicit efficient voiding within minutes of the administration. [ 64 ] This effect is also observed in anesthetized, acute SCI rats. [ 62 ] Chronic administration of NK-2R agonists produces consistent and efficient voiding in SCI rats.…”

Section: P Lasticity Of N Eurotransmitte...mentioning

confidence: 99%

See 1 more Smart Citation

Current Knowledge and Novel Frontiers in Lower Urinary Tract Dysfunction after Spinal Cord Injury

et al. 2022

View full text Add to dashboard Cite

This review article aims to summarize the recent advancement in basic research on lower urinary tract dysfunction (LUTD) following spinal cord injury (SCI) above the sacral level. We particularly focused on the neurophysiologic mechanisms controlling the lower urinary tract (LUT) function and the SCI-induced changes in micturition control in animal models of SCI. The LUT has two main functions, the storage and voiding of urine, that are regulated by a complex neural control system. This neural system coordinates the activity of two functional units in the LUT: the urinary bladder and an outlet including bladder neck, urethra, and striated muscles of the pelvic floor. During the storage phase, the outlet is closed and the bladder is quiescent to maintain a low intravesical pressure and continence, and during the voiding phase, the outlet relaxes and the bladder contracts to promote efficient release of urine. SCI impairs voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter function. Following SCI, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. However, the bladder does not empty efficiently because coordination between the bladder and urethral sphincter is lost. In animal models of SCI, hyperexcitability of silent C-fiber bladder afferents is a major pathophysiological basis of neurogenic LUTD, especially detrusor overactivity. Reflex plasticity is associated with changes in the properties of neuropeptides, neurotrophic factors, or chemical receptors of afferent neurons. Not only C-fiber but also Aδ-fiber could be involved in the emergence of neurogenic LUTD such as detrusor sphincter dyssynergia following SCI. Animal research using disease models helps us to detect the different contributing factors for LUTD due to SCI and to find potential targets for new treatments.

show abstract

Section: P Lasticity Of N Eurotransmitte...mentioning

confidence: 99%

Section: P Lasticity Of N Eurotransmitte...mentioning

confidence: 99%

Current Knowledge and Novel Frontiers in Lower Urinary Tract Dysfunction after Spinal Cord Injury

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Despite its weak ability to displace radiolabeled substance P from recombinant NK1 receptors, NKA is a potent NK1 receptor agonist in functional assays and binds with subnanomolar affinity to a septide-sensitive site on NK1 receptors [ 13 – 15 ]. Activation of NK1 receptors by NKA and related analogs can cause unwanted effects including hypotension [ 9 , 12 , 16 ] and emesis [ 17 ], and so it is important to identify NK2 agonists with a high degree of selectivity for NK2 receptors over septide-sensitive sites on NK1 receptors.…”

Section: Introductionmentioning

confidence: 99%

Affinity, potency, efficacy, and selectivity of neurokinin A analogs at human recombinant NK2 and NK1 receptors

et al. 2018

Self Cite

View full text Add to dashboard Cite

A series of peptide NK2 receptor agonists was evaluated for affinity, potency, efficacy, and selectivity at human recombinant NK2 and NK1 receptors expressed in CHO cells to identify compounds with the greatest separation between NK2 and NK1 receptor agonist activity. Binding studies were performed using displacement of [125I]-NKA binding to NK2 receptors and displacement of [3H]-Septide binding to NK1 receptors expressed in CHO cells. Functional studies examining the increase in intracellular calcium levels and cyclic AMP stimulation were performed using the same cell lines. A correlation was demonstrated between binding affinities (Ki) and potency to increase intracellular calcium (EC50) for NK2 and NK1 receptors. Ranking compounds by their relative affinity (Ki) or potency (EC50) at NK2 or NK1 receptors indicated that the most selective NK2 agonists tested were [Lys5,MeLeu9,Nle10]-NKA(4-10) (NK1/NK2 Ki ratio = 674; NK1/NK2 EC50 ratio = 105) and [Arg5,MeLeu9,Nle10]-NKA(4-10) (NK1/NK2 Ki ratio = 561; NK1/NK2 EC50 ratio = 70). The endogenous peptide, NKA, lacked selectivity with an NK1/NK2 Ki ratio = 20 and NK1/NK2 EC50 ratio = 1. Of the compounds selected for evaluation in cyclic AMP stimulation assays, [β-Ala8]-NKA(4–10) had the greatest selectivity for activation of NK2 over NK1 receptors (NK1/NK2 EC50 ratio = 244), followed by [Lys5,MeLeu9,Nle10]-NKA(4-10) (ratio = 74), and NKA exhibited marginal selectivity (ratio = 2.8).

show abstract

“…NK-2R agonists elicit dose-dependent bladder pressure increases with a quick onset and short duration [95][96][97]. Within minutes of administration, NK-2R agonists induce effective voiding in awake, spinal-intact dogs [97]. This effect is also observed in rats with acute SCI during anesthesia.…”

Section: Neurokininsmentioning

confidence: 93%

“…In addition, NK-2R agonists act as bladder prokinetic agents and induce smoothmuscle contractions by stimulating NK-2R in smooth-muscle cells [93,94]. NK-2R agonists elicit dose-dependent bladder pressure increases with a quick onset and short duration [95][96][97]. Within minutes of administration, NK-2R agonists induce effective voiding in awake, spinal-intact dogs [97].…”

Section: Neurokininsmentioning

confidence: 99%

Molecular Mechanisms of Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury

Shimizu

Saito

Wada

et al. 2023

IJMS

View full text Add to dashboard Cite

This article provides a synopsis of current progress made in fundamental studies of lower urinary tract dysfunction (LUTD) after spinal cord injury (SCI) above the sacral level. Animal models of SCI allowed us to examine the effects of SCI on the micturition control and the underlying neurophysiological processes of SCI-induced LUTD. Urine storage and elimination are the two primary functions of the LUT, which are governed by complicated regulatory mechanisms in the central and peripheral nervous systems. These neural systems control the action of two functional units in the LUT: the urinary bladder and an outlet consisting of the bladder neck, urethral sphincters, and pelvic-floor striated muscles. During the storage phase, the outlet is closed, and the bladder is inactive to maintain a low intravenous pressure and continence. In contrast, during the voiding phase, the outlet relaxes, and the bladder contracts to facilitate adequate urine flow and bladder emptying. SCI disrupts the normal reflex circuits that regulate co-ordinated bladder and urethral sphincter function, leading to involuntary and inefficient voiding. Following SCI, a spinal micturition reflex pathway develops to induce an overactive bladder condition following the initial areflexic phase. In addition, without proper bladder–urethral-sphincter coordination after SCI, the bladder is not emptied as effectively as in the normal condition. Previous studies using animal models of SCI have shown that hyperexcitability of C-fiber bladder afferent pathways is a fundamental pathophysiological mechanism, inducing neurogenic LUTD, especially detrusor overactivity during the storage phase. SCI also induces neurogenic LUTD during the voiding phase, known as detrusor sphincter dyssynergia, likely due to hyperexcitability of Aδ-fiber bladder afferent pathways rather than C-fiber afferents. The molecular mechanisms underlying SCI-induced LUTD are multifactorial; previous studies have identified significant changes in the expression of various molecules in the peripheral organs and afferent nerves projecting to the spinal cord, including growth factors, ion channels, receptors and neurotransmitters. These findings in animal models of SCI and neurogenic LUTD should increase our understanding of pathophysiological mechanisms of LUTD after SCI for the future development of novel therapies for SCI patients with LUTD.

show abstract

[Lys⁵,MeLeu⁹,Nle¹⁰]-NKA_(4–10) Elicits NK2 Receptor–Mediated Micturition and Defecation, and NK1 Receptor–Mediated Emesis and Hypotension, in Conscious Dogs

Cited by 12 publications

References 22 publications

Current Knowledge and Novel Frontiers in Lower Urinary Tract Dysfunction after Spinal Cord Injury

Current Knowledge and Novel Frontiers in Lower Urinary Tract Dysfunction after Spinal Cord Injury

Affinity, potency, efficacy, and selectivity of neurokinin A analogs at human recombinant NK2 and NK1 receptors

Molecular Mechanisms of Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury

Contact Info

Product

Resources

About