Tachykinin Receptor Antagonists and Cough

Several potent and selective antagonists for tachykinin receptors are now available and appear as powerful tools to investigate the physiological and pathological roles of tachykinins and to identify the type of receptor involved in their effect. Indeed, a lot of studies have shown that tachykinin NK₂receptor antagonists (SR 48968, MEN 10627) are able to inhibit cough induced by citric acid, capsaicin or allergen challenge in the unanesthetized guinea-pig or mechanical stimulation of the trachea in the cat. The effects of tachykinin NK₁receptor antagonists are still debated, whereas an inhibitory effect of SR 142801, a tachykinin NK₃receptor antagonist, has been reported against citric acid-induced cough in the guinea-pig. Experiments with tachykinin receptor antagonists which do not cross the blood brain barrier suggest that the site of action of tachykinin receptor antagonists is most probably peripheral, but a central action, at least in an area not protected by the blood brain barrier, cannot be excluded. Finally, tachykinin NK₂receptor stimulation seems to be involved in sensitisation of cough reflex.     

Inhibiting effect of ammonia on citric acid-induced cough in pigs: a possible involvement of substance P

The effect of ammonia on the cough response to citric acid and on substance P release from C-fibers involved in this reflex was assessed. For a period from one to four days, piglets were exposed, in an inhalation chamber, to ammonia at a concentration of 15 or 30 ppm. During exposure, cough induction tests were done every two days. Recovery of the cough reflex after ammonia exposure was also determined. In a separate group of piglets exposed for 2 days to 30 ppm ammonia, substance P content was determined in bronchial and tracheal lavage fluids and in the tracheal and bronchial mucosa. Ammonia (30 ppm) was found to inhibit coughing significantly (the cough frequency was reduced by 64%) after a two-day exposure. In animals exposed for 4 days to this ammonia concentration, the recovery ranged from 3 to 7 days (mean: 5 days). The same ammonia concentration also caused the substance P content to increase significantly in bronchoalveolar lavage fluid (to 432% of its initial value) and tracheal lavage fluid (to 149%) and to decrease significantly in the tracheal mucosa (-58%), however the content in bronchial mucosa was not significantly affected (-43%). Exposure to 15 ppm ammonia had no effect on the frequency of citric acid-induced coughing. In conclusion, ammonia inhibits citric acid-induced coughing in pigs at concentrations that can be detected in piggeries. This inhibitory effect may be related to substance-P depletion in C-fiber endings.     

Effects of specific tachykinin receptor antagonists on citric acid-induced cough and bronchoconstriction in unanesthetized guinea pigs

We compared the effects of a tachykinin NK₁ receptor antagonist, FK888 (N²-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl- -prolyl]-N-methyl-N-phenylmethyl-3-(2-naphtyl)- -alaninamide), and a tachykinin NK₂ receptor antagonist, SR48968 ((S)-N-methyl-N[4-(4-acetylamino-4-phenyl-piperidino)-2-(3,4-dichlorophenyl)butyl]benzamide]), on citric acid-induced cough and bronchoconstriction in conscious guinea pigs. FK888 and SR48968 inhibited the cough dose dependently. Combination of FK888 and SR48968 showed a small additive effect compared with that of FK888 or SR48968 alone. SR48968 but not FK888 inhibited the bronchoconstriction dose dependently. These results indicate that tachykinin NK₁ receptors as well as tachykinin NK₂ receptors are involved in the citric acid-induced cough response. The antitussive activity of the tachykinin NK₁ receptor antagonist appeared not to depend on the anti-bronchoconstrictor effects.     

Inhibiting Effect of Ammonia on Citric Acid‐Induced Cough in Pigs: A Possible Involvement of Substance P

The effect of ammonia on the cough response to citric acid and on substance P release from C‐fibers involved in this reflex was assessed. For a period from one to four days, piglets were exposed, in an inhalation chamber, to ammonia at a concentration of 15 or 30 ppm. During exposure, cough induction tests were done every two days. Recovery of the cough reflex after ammonia exposure was also determined. In a separate group of piglets exposed for 2 days to 30 ppm ammonia, substance P content was determined in bronchial and tracheal lavage fluids and in the tracheal and bronchial mucosa. Ammonia (30 ppm) was found to inhibit coughing significantly (the cough frequency was reduced by 64%) after a two‐day exposure. In animals exposed for 4 days to this ammonia concentration, the recovery ranged from 3 to 7 days (mean: 5 days). The same ammonia concentration also caused the substance P content to increase significantly in broncho‐alveolar lavage fluid (to 432% of its initial value) and tracheal lavage fluid (to 149%) and to decrease significantly in the tracheal mucosa (‐58%), however the content in bronchial mucosa was not significantly affected (?43%). Exposure to 15 ppm ammonia had no effect on the frequency of citric acid‐induced coughing. In conclusion, ammonia inhibits citric acid‐induced coughing in pigs at concentrations that can be detected in piggeries. This inhibitory effect may be related to substance‐P depletion in C‐fiber endings.     

速激肽受体拮抗剂对豚鼠组胺反应的影响

目的：探讨速激肽与组胺（Ｈｉｓ）反应的关系。方法：观察速激肽受体拮抗剂对豚鼠Ｈｉｓ的整体和离体的呼吸道和心血管效应。结果：单用或合用速激肽ＮＫ－１受体拮抗剂ＣＰ－９６３４５（１ｍｇ·ｋｇ－１，ｉｐ）及ＮＫ－２受体拮抗剂ＳＲ－４８９６８（１ｍｇ·ｋｇ－１，ｉｐ）均可显著降低清醒豚鼠吸入Ｈｉｓ气雾的气道反应性。ＣＰ－９６３４５（１ｍｇ·ｋｇ－１，ｉｖ）可显著降低静脉注射Ｈｉｓ引起麻醉豚鼠支气管和心房的伊文思蓝渗出，ＳＲ－４８９６８（１ｍｇ·ｋｇ－１，ｉｖ）则对肺内压升高有较弱的抑制作用，两药对平均动脉压降低无明显作用。在豚鼠的离体气管和支气管平滑肌标本，ＣＰ－９６３４５（１μｍｏｌ·Ｌ－１）及ＳＲ－４８９６８（１μｍｏｌ·Ｌ－１）对Ｈｉｓ的Ｅｍａｘ及ｐＤ２无明显作用。结论：速激肽部分参与了豚鼠的Ｈｉｓ炎症反应，速激肽受体拮抗剂有抗炎作用。     

Contribution of tachykinin receptor subtypes to micturition reflex in guinea pigs

The aim of the present study was to determine the role of tachykinin in the micturition reflex in guinea pigs. We investigated the effects of tachykinin NK(1) receptor antagonists, GR205171 ([2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl-piperidin-3S-yl)-amine), CP99994 ((+), (2R, 3R)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine) and FK888 (N(2)-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl) carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide), the tachykinin NK(2) receptor antagonist, SR48968 ((+)-N-methyl-[4-(4-acetylamino-4-phenyl piperidino)-2-(3, 4-dichloro-phenyl)butyl] benzamide), and the tachykinin NK(3) receptor antagonist, SB223412 ((S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide) on rhythmic bladder contraction. GR205171 and CP99994 but not SR48968 or SB223412 reduced bladder contraction frequency. FK888 inhibited the frequency very slightly at the highest dose tested. The distribution of tachykinin NK(1) receptor antagonists to the central nervous system after intravenous administration was examined using an ex vivo binding assay. GR205171 was distributed to the brain and spinal cord, but the tachykinin NK(1) receptor antagonist, FK888, was not. These results suggest that tachykinin NK(1) receptors, which are located in the central nervous system, play an important role in micturition in guinea pigs.     

The role of substance P and bradykinin in the cough reflex and bronchoconstriction in guinea-pigs

In this study we investigated the ability of aerosolized substance P to induce either cough or bronchoconstriction in guinea-pigs. We have also examined whether pre-treatment, by the inhaled route, of animals with a combination of the neutral endopeptidase inhibitor, phosphoramidon (10(-3) M), and the diaminopeptidase IV inhibitor, diprotin A (10(-3) M), enhances the airway response to substance P. Moreover, we also assessed whether aerosol pre-treatment of guinea-pigs with either substance P or bradykinin, at 10(-4) M, affects the citric acid-induced cough and/or bronchoconstriction. Challenge of guinea-pigs with substance P only at 10(-3) M resulted in significant bronchconstriction but only a weak and variable cough response (1.1+/-0.6; P>0.05). Pre-treatment of guinea-pigs with both phosphoramidon and diprotin A resulted in a small non-significant increase in the cough response (2.8+/-0.9 vs. 1.1+/-0.6; P>0.05) but significantly enhanced substance P-induced bronchoconstriction (P<0.05). Moreover, exposure of guinea-pigs to substance P (10(-4) M) prior to citric acid challenge (0.6 M) resulted in a significant (P<0.05) enhancement of the citric acid-induced bronchoconstriction but not the citric acid-induced cough (11.7+/-1.8 vs. 12.8+/-1.5; P>0.05). In contrast, exposure of guinea-pigs to bradykinin (10(-4) M) prior to the citric acid challenge resulted in a significant enhancement of the cough response (9.2+/-1.9 vs. 25.8+/-2.5; P<0.05) but not the bronchoconstriction (P>0.05). These data do not support a major peripheral role for substance P in the cough reflex, although bradykinin is able to sensitize the cough reflex. Furthermore, these data suggest that bronchoconstriction, induced by citric acid, is not responsible for the cough associated with this irritant.     

Involvement of P2X receptor subtypes in ATP-induced enhancement of the cough reflex sensitivity

We examined the effect of inhaled ATP on the chemical irritant-induced coughs to clarify the roles of ionotropic purinergic receptors in these modulations. Although inhalation of 0.1 M citric acid by itself produced only a few coughs in guinea pigs, exposure to ATP, at concentrations of 3-10 microM, for 2 min concentration-dependently increased the number of 0.1 M citric acid-induced coughs. ATP-induced enhancement of the number of citric acid-induced coughs was abolished when animals were pretreated with 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5-triphosphate (TNP-ATP), an antagonist of P2X receptor subtypes P2X1-4, at a concentration of 50 microM, for 2 min. However, exposure to pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), an antagonist of P2X receptor subtypes P2X1,2,3,5,7, but not of P2X4 receptors, at a concentration of 50 microM, for 2 min, had no effect on the ATP-induced enhancement of the number of citric acid-induced coughs. Furthermore, exposure to reactive blue 2 (RB2, 30 microM, 2 min), an antagonist of P2Y receptors, had no effect on the ATP-induced enhancement of the number of citric acid-induced coughs. Exposure to ATP, at a concentration of 10 microM, for 2 min significantly increased the number of citric acid-induced coughs in capsaicin-pretreated guinea pigs. Furthermore, ATP had no effect on the number of capsaicin-induced coughs in naive animals. These results suggest that although ATP, by itself, does not elicit spontaneous coughs, it likely enhances the cough reflex sensitivity. Furthermore, stimulation of P2X receptors, especially P2X4 receptors, on rapidly adapting receptors may be required for the ATP-induced enhancement of the cough reflex sensitivity.     

'Sensory-efferent' neural control of mucus secretion: characterization using tachykinin receptor antagonists in ferret trachea in vitro.

1. We characterized the tachykinin receptor(s) mediating 'sensory-efferent' neural control of release of 35SO4-labelled macromolecules (mucus) from ferret trachea in vitro in Ussing chambers using selective tachykinin antagonists. Secretion was induced by substance P (SP), neurokinin A (NKA), capsaicin, the NK1 tachykinin receptor agonist [Sar9, Met(O2)11]substance P ([Sar9]SP), or acetylcholine (ACh), or by electrical stimulation of nerves. Antagonists used were FK888 and L-668,169, selective for the NK1 receptor, SR 48968, selective for the NK2 receptor, and FK224, a dual antagonist at NK1 and NK2 receptors. The selectivity of FK888 and SR 48968 was examined on NKA-induced contraction of ferret tracheal smooth muscle in vitro. 2. SP (1 microM) increased mucus secretion by 695% above vehicle controls. FK888 (0.1 microM-30 microM) inhibited SP-induced secretion in a dose-dependent manner, with complete inhibition at 10 microM and an IC50 of 1 microM. L-668,169 (1 microM) also completely inhibited SP-induced secretion. 3. NKA (1 microM) significantly increased mucus secretion by 271% above baseline, a response which was completely inhibited by FK888 (10 microM) or L-668,169 (microM). Secretion induced by ACh (10 microM: 317% above baseline) was not inhibited by FK888 but was inhibited by atropine. Capsaicin (10 microM)-induced secretion (456% above vehicle controls) was significantly inhibited by FK888 and by L-668,169 (111% and 103% inhibition respectively). 4. Electrical stimulation (50 V, 10 Hz, 0.5 ms, 5 min) increased mucus output above baseline (increased by 12 to 26 fold), a response blocked by tetrodotoxin (0.1 microM). FK888 (10 microM) inhibited the increase in secretion due to electrical stimulation by 47%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tachykinin NK3 and NK1 receptor activation elicits secretion from porcine airway submucosal glands

1 We presently characterized the tachykinin receptor subtypes, using tachykinin receptor agonists and selective antagonists, that induce submucosal gland fluid flux (J(G)) from porcine tracheal explants with the hillocks technique. We also investigated the effects of the tachykinin receptor agonists on the electrophysiologic parameters of the tracheal epithelium in Ussing chambers. 2 The NK(1) tachykinin receptor agonist substance P (SP, 1 microM) and the NK(3) tachykinin receptor agonist [MePhe(7)]neurokinin B ([MePhe(7)]NKB, 1 microM) induced gland fluid fluxes of 0.29+/-0.03 microl min(-1) cm(-2) (n=26) and 0.36+/-0.05 microl min(-1) cm(-2) (n=24), respectively; while the NK(2) tachykinin receptor agonist [betaAla(8)]neurokinin A (4-10) ([betaAla(8)]NKA (4-10), 1 microM) had no effect on J(G) (n=10). 3 The NK(1) receptor antagonist CP99994 (1 microM, n=9) blocked 93% of the SP-induced J(G), whereas the NK(3) receptor antagonist SB223412 (1 microM, n=12) had no effect on the SP-induced J(G). However, SB223412 (1 microM, n=9) blocked 89% of the [MePhe(7)]NKB-induced J(G) while CP99994 (1 microM, n=10) did not affect the [MePhe(7)]NKB-induced J(G). The NK(2) receptor antagonist SR48968 (1 microM) did not block the J(G) induced by either the NK(1) (n=4) or NK(3) (n=13) receptor agonists. 4 The nicotinic ganglionic acetylcholine receptor antagonist hexamethonium (1 microM) and the muscarinic acetylcholine receptor antagonist atropine (1 microM) also decreased the NK(3) receptor agonist-induced J(G) by 67% (n=10) and 71% (n=12), respectively. 5 The potential difference (PD), short-circuit current (I(SC)), and membrane resistance (R(M)) of the porcine tracheal epithelial membranes were not significantly affected by any of the neurokinin agonists or antagonists (1 microM, basolateral) used in this study, although SP and [betaAla(8)]NKA (4-10) induced a slight transient epithelial hyperpolarization. 6 These data suggest that NK(1) and NK(3) receptors induce porcine airway gland secretion by different mechanisms and that the NK(3) receptor agonists induced secretion is likely due to activation of prejunctional NK(3) receptors on parasympathetic nerves, resulting in acetylcholine-release. We conclude that tachykinin receptor antagonists may have therapeutic potential in diseases with pathophysiological mucus hypersecretion such as asthma and chronic bronchitis.     

Role of tachykinin NK receptors on the local and remote injuries following ischaemia and reperfusion of the superior mesenteric artery in the rat

Neuropeptides acting on tachykinin NK receptors play an important role in the amplification of inflammatory responses. We have assessed the effects of tachykinin NK receptor blockade on the injuries following intestinal ischaemia and reperfusion (I/R) in rats. The tachykinin NK(1) receptor antagonist SR140333 dose-dependently (0.05 to 0.5 mg kg(-1)) suppressed the local (intestine) and remote (lung) increases in vascular permeability and neutrophil recruitment following mild I/R injury. A structurally-distinct NK(1) receptor antagonist, CP99,994, but not tachykinin NK(2) or NK(3) receptor antagonists also suppressed mild I/R injury. Neonatal pretreatment with capsaicin effectively depleted sensory neurons and abrogated the injuries following mild I/R. Treatment with SR140333 (0.5 mg kg(-1)) significantly reversed severe reperfusion-induced local and remote increases in vascular permeability, neutrophil recruitment, intestinal haemorrhage and blood neutropaenia, but did not prevent the lethality associated with severe I/R. Post-ischaemic treatment with SR140333 significantly inhibited the elevations of TNF-alpha in the intestine and lung, but not serum, following severe I/R. The increase in the concentrations of IL-10 in the lung and serum were also suppressed. Post-ischaemic blockade of tachykinin NK(1) receptors markedly inhibited the local and remote injuries, but not lethality, following reperfusion of the SMA in rats. Neuropeptides, possibly substance P, released from sensory nerves appear to account for the activation of these tachykinin NK(1) receptors. Antagonists of the tachykinin NK(1) receptor may be useful adjuncts in the treatment of the injuries which occur following reperfusion of an ischaemic vascular territory.     

Cigarette smoke increases mucosal permeability in guinea pig trachea via tachykinin NK2 receptor activation

We investigated whether exposure to cigarette smoke increases the mucosal permeability in guinea pig trachea and if this effect could be mediated by tachykinin NK2 receptor activation. Guinea pigs were exposed to either three different doses of cigarette smoke or room air. Mucosal permeability was measured by monitoring the rate of appearance in the circulation of horseradish peroxidase (HRP) that had been instilled into the isolated tracheal segment. Exposure to 20 and 30 puffs but not 10 puffs of cigarette smoke increased the tracheal mucosal permeability. Pretreatment with the tachykinin NK2 receptor antagonist SR48,968 [(S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide] completely inhibited the increase in the permeability of the tracheal mucosa induced by exposure to cigarette smoke, whereas the tachykinin NK1 receptor antagonist SSR240,600 [(R)-2-(1-{2-[4-{2-[3,5-bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl}-4-piperidinyl)-2-methylpropanamide] and the tachykinin NK3 receptor antagonist SR142,801 [(S)-(N)-(1-[3-(1-benzoyl-3(3,4-dichlorophenyl)piperidine-3-yl)propyl]-4-phenylpiperidin-4-yl)-N-methyl-acetamide] had no effect. It is concluded that endogenous tachykinins via NK2 receptor activation mediate the increase in the permeability of the tracheal mucosa induced by exposure to cigarette smoke in guinea pigs.     

The tachykinin NK1 receptor is crucial for the development of non-atopic airway inflammation and hyperresponsiveness

Mast cell activation, bronchoconstriction, inflammation and airway hyperreactivity are prominent features of non-atopic hypersensitivity reactions in mouse airways. We studied the role of tachykinin receptors in mice that were skin-sensitized with dinitrofluorobenzene (or vehicle) and challenged intranasally with dinitrobenzene sulfonic acid. Tachykinin NK1 receptor blockade, by treatment with the antagonist RP67580, or absence of the tachykinin NK1 receptor resulted in a strong reduction in the accumulation of neutrophils in the bronchoalveolar lavage fluid, and in the development of tracheal hyperreactivity in mice 48 h after challenge. In contrast, treatment with the tachykinin NK2 receptor antagonist SR48968 did not affect the dinitrofluorobenzene-induced hypersensitivity reaction. We have previously shown that mast cells play a crucial role in the development of non-atopic asthma. However, we did not observe an inhibitory effect of the tachykinin receptor antagonists or the genetic absence of tachykinin NK1 receptors on mast cell protease release. In conclusion, distal from mast cell activation, the tachykinin NK1 receptor is crucial for the infiltration of pulmonary neutrophils and the development of tracheal hyperreactivity in non-atopic asthma.     

Tachykinin NK1 receptor subtypes in the rat urinary bladder.

1. Following the recent proposal that the selective agonist septide, ([pGlu6,Pro9]SP(6-11)), acts on a novel tachykinin receptor distinct from the ''classical'' NK1 receptor, the aim of the study was to investigate the possible heterogeneity of tachykinin NK1 receptors in the rat urinary bladder. 2. The synthetic tachykinin receptor agonists, septide (pD2 7.87) and [Sar9]substance P (SP) sulphone (pD2 7.64) produced concentration-dependent contractions of the rat isolated urinary bladder. 3. The NK1 receptor antagonists GR82,334, (+/-)-CP96,345, and RP67,580 competitively antagonized (slopes of Schild plot not significantly different from unity) the response to septide with the rank order of potency (pKB values in parentheses): RP 67,580 (7.57) > GR 82,334 (7.01) > (+/-)-CP 96,345 (6.80). The same antagonists were significantly less potent when tested against [Sar9]SP sulphone, while maintaining the same rank order of potency: RP 67,580 (7.00) > GR 82,334 (5.93) > (+/-)-CP 96,345 (< 6). The antagonists did not affect the concentration-response curve to bombesin. 4. To exclude the involvement of the NK2 receptor, a second series of experiments was performed in the presence of the potent nonpeptide NK2 receptor antagonist, SR 48,968. SR 48,968 (1 microM) produced a rightward shift of the concentration-response curve to the NK2 receptor selective agonist, [beta Ala8]neurokinin A (NKA) (4-10). SR 48,968 did not significantly modify the response to SP, NKA, neurokinin B (NKB), neuropeptide K (NPK), neuropeptide gamma (NP gamma), SP(4-11), SP(6-11), septide or [Sar9]SP sulphone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tachykinin NK(3) receptor agonists induced microvascular leakage hypersensitivity in the guinea-pig airways.

Microvascular leakage hypersensitivity is a main component of neurogenic inflammation and of tachykinin effects.The aim of this study was to examine the ability of neurokinin B and of the tachykinin NK(3) receptor agonists, [MePhe(7)]neurokinin B or senktide, to potentiate when given by aerosol the microvascular leakage induced by histamine in guinea-pig airways and to compare their effects to those of tachykinin NK(1) (substance P, [Sar(9),Met(O(2))(11)]substance P) or tachykinin NK(2) (neurokinin A, [betaAla(8)]neurokinin A (4-10)) receptor agonists. Guinea-pigs were pretreated successively for 10 min with aerolized salbutamol and phosphoramidon; 15 min later, they were exposed for 30 min to an aerosolized solution of tachykinin receptor agonists; 24 h later, the animals were anaesthetized and vascular permeability was quantified by extravasation of Evans blue dye. Neurokinin B, [MePhe(7)]neurokinin B and senktide (3 x 10(-6)-3 x 10(-5)M) induced a potentiation of the effects of histamine on the vascular permeability in the trachea and main bronchi. Compared to other tachykinin NK(1) and NK(2) receptor agonists, the order of potency was: senktide>neurokinin B=[Sar(9),Met(O(2))(11)]substance P=[betaAla(8)]neurokinin A (4-10)=[MePhe(7)]neurokinin B>neurokinin A>substance P. The potentiation by [MePhe(7)]neurokinin B of histamine-induced microvascular leakage was abolished by the tachykinin NK(1) receptor antagonist SR140333 ([(S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)piperidin-3-yl]etyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane, chloride]) or the tachykinin NK(3) receptor antagonists SR 142801 ([(R)-(N)-(1-(3-(l-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide]) and SB 223412 ([(S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide]). In conclusion, these results suggest that tachykinin NK(3) receptors might be involved in the potentiation of histamine-induced increase in microvascular permeability.     

Involvement of ionotropic purinergic receptors in the histamine-induced enhancement of the cough reflex sensitivity in guinea pigs

We examined the effect of inhaled histamine on citric acid-induced coughs and clarified the role of ionotropic purinergic receptors in the resulting changes. Although the inhalation of 0.1 M citric acid by itself produced only a few coughs in guinea pigs, exposure to histamine, at concentrations of 0.3 to 1 mM, for 2 min concentration dependently increased the number of citric acid-induced coughs. This histamine-induced increase in the number of citric acid-induced coughs was dose dependently and significantly reduced when animals were pretreated with fexofenadine, a histamine H1 receptor antagonist. The histamine-induced increase in the number of citric acid-induced coughs was completely reduced when animals were co-pretreated with 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5-triphosphate (TNP-ATP, 50 microM), a P2X receptor antagonist, and reactive blue 2, a P2Y receptor antagonist, for 2 min. Furthermore, the ATP-induced increase in the number of citric acid-induced coughs was dose dependently and significantly decreased when animals were pretreated with fexofenadine, at doses of 0.3, 1 and 3 mg/kg, p.o. These results suggest that histamine enhances the excitability of rapidly adapting receptors to tussive stimuli via modulation of ATP release in the airways. Furthermore, ATP might act not only on P2X receptors to directly activate rapidly adapting receptors, but also on P2Y receptors to increase histamine release, indirectly increasing the cough reflex sensitivity.     

NK2 receptors mediate tachykinin-induced contractions of rat uterus during the oestrous cycle.

We examined tachykinin-induced contractions of uteri from rats during the oestrous cycle. The potencies of substance P, neurokinin A, neurokinin B and the tachykinin NK2 receptor-selective agonist, [Lys5, MeLeu9, Nle10] neurokinin A-(4-10), and of the non-peptide tachykinin NK1, NK2 and NK3 receptor antagonists (S)1-[2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)pip eridin-3-yl]ethyl]-4phenyl-1-azonia-bicyclo[2.2.2]octane (SR 140333), (S)-N-methyl-N [4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzam ide (SR 48968) and (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)prop yl)-4-phenylpiperidin-4-yl)-N-methylacetamide (SR 142801), were examined. The relative agonist potencies, i.e., [Lys5, MeLeu9, Nle10] neurokinin A-(4-10) > or = neurokinin A > neurokinin B > or = substance P were similar in preparations from rats in dioestrus/metoestrus and those in proestrus/oestrus. Apparent pK(B) values for SR 48968 versus neurokinin A and [Lys5, MeLeu9, Nle10] neurokinin A-(4-10), were 9.9 and 9.2, respectively, indicating activation of an NK2 receptor. SR 140333 (10 nM) produced only a small rightward shift of the log concentration-response curve to substance P. SR 48968 (3 nM), but not SR 142801 (100-300 nM) reduced the effect of neurokinin B. These data indicate that in the rat tachykinin-induced contractions of the uteri during the oestrous cycle are mediated primarily by tachykinin NK2 receptors, and that fluctuations in ovarian hormonal levels during the oestrous cycle have little influence on the uterine response to tachykinins.     

Inhibition of guinea-pig and human sensory nerve activity and the cough reflex in guinea-pigs by cannabinoid (CB2) receptor activation

1. There is considerable interest in novel therapies for cough, since currently used agents such as codeine have limited beneficial value due to the associated side effects. Sensory nerves in the airways mediate the cough reflex via activation of C-fibres and RARs. Evidence suggests that cannabinoids may inhibit sensory nerve-mediated responses. 2. We have investigated the inhibitory actions of cannabinoids on sensory nerve depolarisation mediated by capsaicin, hypertonic saline and PGE2 on isolated guinea-pig and human vagus nerve preparations, and the cough reflex in conscious guinea-pigs. 3. The non-selective cannabinoid (CB) receptor agonist, CP 55940, and the selective CB2 agonist, JWH 133 inhibited sensory nerve depolarisations of the guinea-pig vagus nerve induced by hypertonic saline, capsaicin and PGE2. These responses were abolished by the CB2 receptor antagonist SR144528, and unaffected by the CB1 antagonist SR141716A. Similarly, JWH 133 inhibited capsaicin-evoked nerve depolarisations in the human vagus nerve, and was prevented by SR144528. 4. Using a guinea-pig in vivo model of cough, JWH 133 (10 mg kg-1, i.p., 20 min) significantly reduced citric acid-induced cough in conscious guinea pigs compared to those treated with the vehicle control. 5. These data show that activation of the CB2 receptor subtype inhibits sensory nerve activation of guinea-pig and human vagus nerve, and the cough reflex in guinea-pigs, suggesting that the development of CB2 agonists, devoid of CB1-mediated central effects, will provide a new and safe antitussive treatment for chronic cough.     

The tachykinin NK1 receptor in the brain: pharmacology and putative functions.

After its discovery in 1931, substance P (SP) remained the only mammalian member of the family of tachykinin peptides for several decades. Tachykinins thus refer to peptides sharing the common C-terminal amino acid sequence Phe-X-Gly-Leu-Met x NH2. In recent years the family of mammalian tachykinins has grown with the isolation of two novel peptides from bovine and porcine central nervous system (CNS), neurokinin A and neurokinin B. In parallel with the identification of multiple endogenous tachykinins several classes of tachykinin receptors were discovered. The receptors described so far are named tachykinin NK1 receptor, tachykinin NK2 receptor and tachykinin NK1 receptor, respectively. The present review focuses on the pharmacology and putative function of tachykinin NK1 receptors in brain. The natural ligand with the highest affinity for the tachykinin NK1 receptor is SP itself. The C-terminal sequence is essential for activity, the minimum length of a fragment with reasonable affinity for the tachykinin NK1 receptor is the C-terminal hexapeptide. A rapid advance of knowledge was caused by development of non-peptidic tachykinin NK1 receptor antagonists. This area is under rapid development and a variety of different chemical classes of compounds are involved. Species-dependent affinities of tachykinin NK1 receptor antagonists reveal two clusters of compounds, targeting the tachykinin NK1 receptor subtype found in guinea pig, human or ferret or the one in rat or mouse, respectively. The most recently developed compounds are highly selective, enter the brain and are orally bioavailable. Distinct behavioural effects in experimental animals suggest the involvement of tachykinin NK1 receptors in nociceptive transmission, basal ganglia function or anxiety and depression. Recent clinical trials in man showed that tachykinin NK1 receptor antagonists are effective in treating depression and chemotherapy-induced emesis. Therefore, it is well possible that tachykinin NK1 receptor antagonists will be clinically used for treatment of specific CNS disorders within a short period of time.     

Cardiovascular responses to rat/mouse hemokinin-1, a mammalian tachykinin peptide: systemic study in anesthetized rats

Rat/mouse hemokinin-1 is a mammalian tachykinin peptide whose biological functions have not been well characterized. In the present study, an attempt has been made to investigate the effect and mechanism of action of rat/mouse hemokinin-1 on systemic arterial pressure after intravenous (i.v.) injections in anesthetized rats by comparing it with that of substance P. Our data showed that injection of rat/mouse hemokinin-1 (0.1, 0.3, 1, 3 and 10 nmol/kg) lowered systemic arterial pressure dose-dependently. This effect was significantly blocked by pretreatment with SR140333 (a selective tachykinin NK1 receptor antagonist) and the NO synthase inhibitor L-NAME (Nomega-nitro-L-arginine methyl ester hydrochloride), respectively, but was not affected by bilateral vagotomy or the muscarinic receptor blocker atropine. Compared to rat/mouse hemokinin-1, a dose of 3 nmol/kg of substance P caused biphasic changes in systemic arterial pressure (depressor and pressor responses). The results suggest that the mechanism of the depressor response caused by substance P was similar to rat/mouse hemokinin-1 in that it was inhibited by SR140333 and L-NAME, respectively, but that there was a component of the cardiovascular change induced by rat/mouse hemokinin-1 (but not substance P) that was attenuated by SR48968 (a selective tachykinin NK2 receptor antagonist). The depressor response induced by rat/mouse hemokinin-1 (i.v.) might be explained primarily by the action on endothelial tachykinin NK1 receptors to release endothelium-derived relaxing factor (NO) and this effect was not affected by vagal components. In addition, rat/mouse hemokinin-1 could not induce the pressor response through stimulation of sympathetic ganglion like substance P in anesthetized rats.