Evidence for Substance P as an Endogenous Substance Causing Cough in Guinea Pigs

Ujiie, Y; Sekizawa, Kiyohisa; Aikawa, Tatsuo; Sasaki, Hidetada

doi:10.1164/ajrccm/148.6_pt_1.1628

Cited by 93 publications

(62 citation statements)

References 28 publications

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“…The swallowing reflex is controlled by SP, which is synthesized in the sensory ganglia of the pharynx (Ujiie et al, 1993). However, evaluation of the swallowing function is performed by endoscopy or angiography.…”

Section: Discussionmentioning

confidence: 99%

“…The swallowing reflex is controlled by substance P (SP), which is released from nerve endings in the mucosa and mouth (Sasaki, 2002;Jin et al, 1994;Ujiie et al, 1993), under normal conditions. Swallowing dysfunction can be caused by a decrease in the production of dopamine and SP.…”

Section: Introductionmentioning

confidence: 99%

“…SP released from nerve endings in the mucosa and mouth is derived from the influx of Ca 2+ into the cell because of the activation of TRPV1 (Sasaki, 2002;Jin et al, 1994;Ujiie et al, 1993), which then promotes secretion of SP (Widdicombe, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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“…This cough did not respond to NK 1 receptor antagonists (R116301 and GR-203040), a NK 2 receptor antagonist (saredutant), or a mixed NK 1 /NK 2 receptor antagonist (MDL-103392). This might be surprising since NK 1 receptor antagonists have been found effective against cough induced by SP and other stimuli (Ujiie et al, 1993;Fahy et al, 1995;Sekizawa et al, 1996). In agreement with its well known antitussive effect (Adcock et al, 1988), the opioid codeine was able to block the [␤ALA 8 ]-NKA (4 -10)-induced cough.…”

Section: Discussionmentioning

confidence: 94%

Pharmacological Profile of (2R-trans)-4-[1-[3,5-bis(Trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate (R116301), an Orally and Centrally Active Neurokinin-1 Receptor Antagonist

Megens¹,

Ashton²,

Vermeire³

et al. 2002

J Pharmacol Exp Ther

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In comparison with a series of reference compounds, (2R-trans)-4-[1- [3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate (R116301) was characterized as a specific, orally, and centrally active neurokinin-1 (NK 1 ) receptor antagonist with subnanomolar affinity for the human NK 1 receptor (K i : 0.45 nM) and over 200-fold selectivity toward NK 2 and NK 3 receptors. R116301 inhibited substance P (SP)-induced peripheral effects (skin reactions and plasma extravasation in guinea pigs) and a central effect (thumping in gerbils) at low doses (0.08 -0.16 mg/kg, s.c. or i.p.), reflecting its high potency as an NK 1 receptor antagonist and excellent brain disposition. Higher doses blocked various emetic stimuli in ferrets, cats, and dogs (ED 50 values: 3.2 mg/kg, s.c.; 0.72-2.5 mg/kg, p.o.). Even higher doses (11-25 mg/kg, s.c.) were required in mice (capsaicin-induced ear edema) and rats (SP-induced extravasation and salivation), consistent with lower affinity for the rodent NK 1 receptor and known species differences in NK 1 receptor interactions. R116301 inhibited the ocular discharge (0.034 mg/kg) but not the dyspnoea, lethality, or cough (Ͼ40 mg/kg, s.c.) induced by [␤ALA 8 ]-neurokinin A (NKA) (4 -10) in guinea pigs, attesting to NK 1 over NK 2 selectivity. R116301 did not affect senktide-induced miosis (Ͼ5 mg/kg, s.c.) in rabbits, confirming the absence of an interaction with the NK 3 receptor. R116301 was inactive in guinea pigs against skin reactions induced by histamine, platelet-aggregating factor, bradykinin, or Ascaris allergens (Ͼ10 mg/kg, s.c.). In all species, R116301 showed excellent oral over parenteral activity (ratio, 0.22-2.7) and a relatively long duration (6.5-16 h, p.o.). The data attest to the specificity and sensitivity of the animal models and support a role of NK 1 receptors in various diseases.Tachykinins belong to a family of short peptides that are widely distributed in the mammalian central and peripheral nervous system (Lundberg, 1995;Maggi, 1995;Bertrand and Geppetti, 1996). They share the common C-terminal sequence Phe-Xaa-Gly-Leu-Met-NH 2 . Tachykinins released from peripheral sensory nerve endings are believed to be involved in neurogenic inflammation. In the spinal cord/central nervous system, tachykinins may play a role in pain transmission/perception and in some autonomic reflexes and behaviors. The three major tachykinins are substance P (SP), neurokinin (NK) A and NKB with preferential affinity for three distinct receptor subtypes, termed NK 1 , NK 2 , and NK 3 , respectively. However, functional studies on cloned receptors suggest strong functional cross-interaction between the three Article, publication date, and citation information can be found at

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“…NEP inhibitors also potentiate substance P-induced plasma extravasation (Borson et al 1989) and cough (Kohrogi et al 1988). Furthermore, intraperitoneal injection of phosphoramidon induced cough in guinea pigs that was completely inhibited by a specific NK1 receptor antagonist (Ujiie et al 1993), providing the evidence that substance P released from sensory nerves in the airway is an endogenous substance causing cough in the body. In airway epithelium, substance P increases short-circuit current (Al-Bazzaz et al 1985) and stimulates chloride secretion (Mizoguchi and Hicks 1989), effects that are potentiated by NEP inhibitors (Mizoguchi and Hicks 1989).…”

mentioning

confidence: 87%

Evidence for Substance P as an Endogenous Substance Causing Cough in Guinea Pigs

Cited by 93 publications

References 28 publications

Swallowing Function Improvement Effect of Ginger <i>(Zingiber officinale)</i>

Swallowing Function Improvement Effect of Ginger <i>(Zingiber officinale)</i>

Pharmacological Profile of (2R-trans)-4-[1-[3,5-bis(Trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate (R116301), an Orally and Centrally Active Neurokinin-1 Receptor Antagonist

Enzymatic Modulation of Bronchoconstriction, Gland Secretion, Plasma Extravasation and Cough.

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