A novel tachykinin NK2 receptor antagonist prevents motility‐stimulating effects of neurokinin A in small intestine

Lördal, Mikael; Navalesi, Giovanni; Theodorsson, Elvar; Maggi, Carlo Alberto; Hellström, Per M.

doi:10.1038/sj.bjp.0704217

Cited by 73 publications

(48 citation statements)

References 34 publications

(41 reference statements)

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“…Jaafari et al (22) reported that TACR2 alpha mRNA encoding NK 2 -R was predominantly expressed in the normal human colon. Furthermore, Lordal et al (23,24) demonstrated that intravenous infusion of NKA in healthy volunteers could induce marked contraction of the small intestine and was inhibited by the NK 2 -Rselective antagonist nepadutant. These results strongly support our findings and suggest that our in vitro findings could translate into an in vivo clinical setting.…”

Section: Vehicle Atropinementioning

confidence: 99%

Bidirectional Regulation of Human Colonic Smooth Muscle Contractility by Tachykinin NK2 Receptors

Nakamura

Tanaka²,

Imanishi

et al. 2011

J Pharmacol Sci

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Abstract. In this study, we attempted to clarify the mechanism of tachykinin-induced motor response in isolated smooth muscle preparations of the human colon. Fresh specimens of normal colon were obtained from patients suffering from colonic cancer. Using mucosa-free smooth muscle strips, smooth muscle tension with circular direction was monitored isometrically. Substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) produced marked contraction. All of these contractions were inhibited by saredutant, a selective NK 2 -R antagonist, but not by CP122721, a selective NK 1 -R antagonist or talnetant, a selective NK 3 -R antagonist. βAla 8 -NKA(4-10) induced concentration-dependent contraction similar to NKA, but Sar 9 -Met 11 -SP and Met-Phe 7 -NKB did not cause marked contraction. Colonic contraction induced by βAla 8 -NKA(4-10) was completely blocked by saredutant, but not by atropine. Tetrodotoxin or N G -nitro-L-arginine methyl ester pretreatment significantly enhanced βAla 8 -NKA(4-10)-induced contraction. Immunohistochemical analysis showed that the NK 2 -R was expressed on the smooth muscle layers and myenteric plexus where it was also co-expressed with neuronal nitric oxide synthase in the myenteric plexus. These results suggest that the NK 2 -R is a major contributor to tachykinin-induced smooth muscle contraction in human colon and that the NK 2 -R-mediated response consists of an excitatory component via direct action on the smooth muscle and an inhibitory component possibly via nitric oxide neurons.

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Section: Vehicle Atropinementioning

confidence: 99%

Bidirectional Regulation of Human Colonic Smooth Muscle Contractility by Tachykinin NK2 Receptors

Nakamura

Tanaka²,

Imanishi

et al. 2011

J Pharmacol Sci

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“…Clinical data is currently deficient. However, in one study of healthy volunteers using the selective NK2 antagonist nepadutant (MEN11420), IBS-like symptoms triggered by the infusion of neurokinin A were reduced [108] . Saredutant (SR48968), another NK2 antag onist, is also being developed for the treatment of IBS, but clinical results are not yet available.…”

Section: Neurokinin Antagonistsmentioning

confidence: 99%

Updates on treatment of irritable bowel syndrome

Hammerle¹,

Surawicz²

2008

WJG

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Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder characterized by abdominal pain and discomfort in association with altered bowel habits. It is estimated to affect 10%-15% of the Western population, and has a large impact on quality of life and (in)direct healthcare costs. IBS is a multifactorial disorder involving dysregulation within the brain-gut axis, and it is frequently associated with gastrointestinal motor and sensory dysfunction, enteric and central nervous system irregularities, neuroimmune dysregulation, and postinfectious inflammation. As with other functional medical disorders, the treatment for IBS can be challenging. Conventional therapy for those with moderate to severe symptoms is largely unsatisfactory, and the development of new and effective drugs is made difficult by the complex pathogenesis, variety of symptoms, and lack of objective clinical findings that are the hallmark of this disorder. Fortunately, research advances over the past several decades have provided insight into potential mechanisms responsible for the pathogenesis of IBS, and have led to the development of several promising pharmaceutical agents. In recent years there has been much publicity over several of these new IBS medications (alosetron and tegaserod) because of their reported association with ischemic colitis and cardiovascular disease. While these agents remain available for use under restricted prescribing programs, this highlights the need for continued development of safe and effective medication for IBS. This article provides a physiologicallybased overview of recently developed and frequently employed pharmaceutical agents used to treat IBS, and discusses some non-pharmaceutical options that may be beneficial in this disorder.

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“…NK1 receptors seem to be primarily involved in the physiological control of motility, whereas NK2 receptors seem to exert a prominent role in inflammation and control of motility in pathological conditions (Lecci et al, 1994;Holzer and Holzer-Petsche, 1997;Lecci et al, 1997;Maggi, 1997). For example, NK2 receptor antagonists can exert prominent effects on abdominal cramping or the number of intestinal contractions evoked by rectal distension (Julia et al, 1994;Santicioli et al, 1997;Toulouse et al, 2000;Lordal et al, 2001;Patacchini and Maggi, 2001). …”

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confidence: 99%

Effect of Nepadutant, a Neurokinin 2 Tachykinin Receptor Antagonist, on Immediate-Early Gene Expression after Trinitrobenzenesulfonic Acid-Induced Colitis in the Rat

Birder

Kiss²,

Groat³

et al. 2003

J Pharmacol Exp Ther

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Tachykinins have been implicated in inflammatory responses such as those occurring in inflammatory bowel disease. Accordingly, we investigated the effect of a selective neurokinin (NK) 2 receptor antagonist, nepadutant, on proto-oncogene expression in the L 6 -S 1 spinal cord as well as in dorsal root ganglion (DRG) neurons after either non-noxious colorectal distension (CRD) or trinitrobenzenesulfonic acid (TNBS)-induced colitis in the adult rat. In both preparations, c-fos was expressed in similar spinal cord regions, including medial and lateral dorsal horn, dorsal commissure (DCM; laminae X above the central canal), and the sacral parasympathetic nucleus (SPN, laminae V-VII). However, TNBS-induced colitis produced significantly larger numbers (8 -10-fold increase over control) of Fos-positive spinal cord neurons. In addition, there was also a significant increase (3-4-fold) in the number of Jun-positive colon DRG neurons after colitis compared with CRD. Nepadutant had no significant effect on proto-oncogene expression induced by CRD in either spinal cord neurons or DRG neurons. In contrast, nepadutant significantly decreased (70%) the number of Fos-positive neurons in dorsal horn, DCM, and SPN spinal cord regions and significantly decreased (75%) the number of Jun-positive DRG neurons after TNBS-induced irritation of the colon. These findings indicate that nepadutant suppresses the responses of colonic afferent neurons to nociceptive stimuli and that NK2 receptor antagonists may be beneficial in the treatment of sensory symptoms of colitis.Inflammatory bowel disease is often associated with increased painful sensations in response to colorectal disten-

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A novel tachykinin NK2 receptor antagonist prevents motility‐stimulating effects of neurokinin A in small intestine

Cited by 73 publications

References 34 publications

Bidirectional Regulation of Human Colonic Smooth Muscle Contractility by Tachykinin NK2 Receptors

Bidirectional Regulation of Human Colonic Smooth Muscle Contractility by Tachykinin NK2 Receptors

Updates on treatment of irritable bowel syndrome

Effect of Nepadutant, a Neurokinin 2 Tachykinin Receptor Antagonist, on Immediate-Early Gene Expression after Trinitrobenzenesulfonic Acid-Induced Colitis in the Rat

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