how does bradykinin cause cough

Transient receptor potential cation channels in disease. Our data is also in keeping with the central effects of BK in hyperalgesia. administered 12-LOX inhibitor, baicalein (BA) 30 mole ml1 (n=6) and 100 mole ml1 (n=5), versus vehicle (n=6), on BK-enhanced citric acid-induced cough (a) changes in Penh (b) and Penh AUC (c). Group 1 was pretreated with the vehicle of thebradykinin antagonist (HOE-140). Naunyn Schmiedeberg's Arch Pharmacol. Additional bradykinin inhibitors exist. Normally distributed data were assessed by either one-way analysis of variance ANOVA followed by Bonferroni post hoc test or by Students t-test. Morice AH, Millqvist E, Belvisi MG, Bieksiene K, Birring SS, Chung KF, et al. 2004;41(6):84957. Hu H, Tian J, Zhu Y, Wang C, Xiao R, Herz JM, et al. Values represent means+sem. Chronic cough is a poorly understood and managed clinical problem with a high prevalence rate [21, 88]. A local accumulation of bradykinin may lead to activation of pro-inflammatory peptides (e.g. In this study we show, using a conscious guinea-pig model of cough, that centrally administered BK sensitizes the cough reflex via B2 receptors. Group 1 was pretreated with the vehicle of theTRPV1 antagonist (JNJ-17203212). Cough Gees M, Owsianik G, Nilius B, Voets T. TRP channels. Briefly, prior to cough assessment, the dummy cannula was removed from the guide cannula. https://doi.org/10.1186/s12931-019-1060-8, DOI: https://doi.org/10.1186/s12931-019-1060-8. Chest. 1b and c). Am J Respir Crit Care Med. 2005;493(4):596606. Angiotensin-Converting Enzyme Inhibitor-Induced Cough Synergistic interactions between airway afferent nerve subtypes mediating reflex bronchospasm in Guinea pigs. Ann N Y Acad Sci. One of lisinoprils most well-known side effects is a dry cough. 20, and the skull was cleaned with 3% hydrogen peroxide. Based on the significant enhancement of BK at 0.06 nmole ml1 on both cough and Penh, this dose was chosen for the rest of the experiments in this study. substance P, neuropeptide Y) and a local release of histamine. BK is an important inflammatory mediator that has been shown to be involved in cough mechanisms. Fogari R, Zoppi A, Tettamanti F, Malamani GD, Tinelli C, Salvetti A. PubMed Central Direct activation of the ion channel TRPA1 by Ca2+. Of interest, several studies have reported that both TRPV1 and TRPA1 channels are co-expressed on sensory and dorsal root ganglia (DRG) neurons [38, 59, 75, 76]. 2005;98(6):196182. Animals were arbitrarily divided into 3 groups (n=68). Indomethacin, at 80 but not 30 nmole ml1, significantly inhibited the BK-enhancement of cough following citric acid challenge by 70% (P<0.05; Fig. However, itis possible that BK stimulates a specific set of second order neurons in the nTS which in turn activate the airway-related vagal preganglionic neuron (AVPNs). Cough is one of the common adverse effects in patients receiving angiotensin-converting enzyme inhibitors (ACEIs). Lung. Hewitt MM, Adams G Jr, Mazzone SB, Mori N, Yu L, Canning BJ. Involvement of glutamate in transmission of afferent constrictive inputs from the airways to the nucleus tractus solitarius in ferrets. Pulm Pharmacol Ther. Compr Physiol. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Fifteen min after infusion of BK, all animals were exposed to aerosolized citric acid (0.2M) for 10min. Our findings show that central BK administration sensitizes cough and enhances airway obstruction via a B2 receptor/TRPV1 and/or TRPA1 channels which are coupled via metabolites of COX and/or 12-LOX enzymes. Melzack R, Coderre TJ, Katz J, Vaccarino AL. 2002;22(18):82229. Values represent means+sem. In support of this, BK has been previously shown to activate TRPV1 receptors via a 12-HPETE-dependent mechanism. The findings in this study may have relevance to patients with chronic cough where theirdemonstrated CHS could be, at least, partly due to enhanced central activity of the BK/B2receptor/TRPV1/TRPA1 signaling pathway and suggest that blockade of central B2 receptors or concurrent inhibition of TRPV1/TRPA1 channels or COX/12-LOX enzymes may offer novel therapeutic treatment approaches for these patients. Quora - A place to share knowledge and better understand the This study compares reports of cough with losartan and three ACEIs used in general practice. administered non-selective COX inhibitor, indomethacin (INDO) 30 nmole ml1 (n=5) and 80 nmole ml1 (n=6), versus vehicle (n=10), on BK-enhanced citric acid-induced cough (a) changes in Penh (b) and Penh AUC (c). For example, meclofenamic acid pretreatment failed to attenuate the inhaled BK-evoked cough [50]. Drugs were administered as previously described [29]. 2003;552(Pt 2):54759. 2011;300(2):R36977. 1992;117(1):3741. [15], Low levels of bradykinin in the body correlate to a high body mass index in adolescents; it has been proposed that bradykinin can be used as a biomarker for metabolic syndrome. The later the cough occurs during treatment, the less often the drug is the causative agent and the cough and also less likely to disappear after discontinuation of ramipril. Kosugi M, Nakatsuka T, Fujita T, Kuroda Y, Kumamoto E. Activation of TRPA1 channel facilitates excitatory synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord. Discovery of ML351, a potent and selective inhibitor of human 15-Lipoxygenase-1. A midline incision in the skin above the skull (2cm) was made with a sharp surgical blade No. route, dose-dependently enhanced the citric acid-induced cough and airway obstruction. Maher SA, Birrell MA, Belvisi MG. Prostaglandin E2 mediates cough via the EP3 receptor: implications for future disease therapy. 2008;176(2):2329. CAS Animals were arbitrarily divided into three groups (n=813). Foucquier J, Guedj M. Analysis of drug combinations: current methodological landscape. Animals were arbitrarily divided into three groups (n=79). Haxhiu MA, Kc P, Moore CT, Acquah SS, Wilson CG, Zaidi SI, et al. These included some animals removing their cannula at different stages in the experiment, in addition to the anesthesia-induced death in some animals. J Neurosci. PubMed Carr MJ, Kollarik M, Meeker SN, Undem BJ. CAS [20], Bradykinin has been proposed as an explanation for many symptoms associated with COVID-19, including dry coughs, myalgia, fatigue, nausea, vomiting, diarrhea, anorexia, headaches, decreased cognitive function, arrhythmia and sudden cardiac death. The infusion cannula was connected to the guide cannula and to a Hamilton syringe pump-model (Harvard Apparatus, USA) via a polyethylene tubing (PE-20). A pneumotachograph, with defined resistance in the wall of the main chamber acted as low-pass filter and allows thermal compensation. 1b and c). administered BK (0.03 and 0.06 nmole ml1; n=5 and 9, respectively), versus vehicle (n=8), on citric acid-induced cough (a) changes inPenh (b) and Penh AUC (c). Citric acid (0.2M) was dissolved in PBS. substance P, neuropeptide Y) and a local release of histamine. How does increased bradykinin cause cough? idswater.com Penh is a dimensionless value that reflects changes in the waveform of the box pressure signal from both inspiration and expiration (PIP, PEP) and combines it with the timing comparison of early and late expiration (Pause). 2013;14(3):24960. It would be ironic if ARBs some how caused an increase in cough relative to the prils. In house-bred Dunkin-Hartley guinea pigs (400600g) of either sex were maintained under temperature controlled conditions with a 12-h light/dark cycle with free access to standard chow and water ad libitum. Stock solution of BK and HOE-140 were initially prepared by dissolving in ACSF and subsequent dilutions were made using the same solvent. Activation of the midbrain periaqueductal gray induces airway smooth muscle relaxation. Gammon CM, Allen AC, Morell P. Bradykinin stimulates phosphoinositide hydrolysis and mobilization of arachidonic acid in dorsal root ganglion neurons. 1995;40(5):4239. The total number of guinea pigs used in the study was 171. Neuron. Similar to the cough effects, pretreatment with HOE-140 also significantly blocked BK-enhancement of airway obstruction indicating that this response was also mediated via the B2 receptor. Anesthesiology. Pulm Pharmacol Ther. Transient receptor potential ankyrin 1 receptor activation in vitro and in vivo by pro-tussive agents: GRC 17536 as a promising anti-tussive therapeutic. Anti-tussive and bronchodilator mechanisms of action for the enaminone E121. 2014;119(1):17985. Which blood pressure medications cause coughing? Fifteen min after infusion of BK, all animals were exposed to aerosolized citric acid (0.2M) for 10min. Effects. [23] Other substances that act as bradykinin inhibitors include aloe[24][25] and polyphenols, substances found in red wine and green tea.[26]. This may also Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, et al. Number of coughs measured during a 20-min period were expressed as meanstandard error of the mean (SEM). These findings are in line with data showing a role for both TRPV1 and TRPA1 in inhaledBK-induced cough [39]. Treatment with JNJ-17203212, at only 3 but not 1 mole ml1, significantly inhibited the BK-enhancement of cough following citric acid challenge by 75% (P<0.05; Fig. It is thought that bradykinin is converted to inactive metabolites by ACE, therefore inhibition of this enzyme leads to increased levels of bradykinin; increased bradykinin sensitizes somatosensory fibers and thus causes hyperalgesia. Similarly, substance P(SP) microinjected into the nTS has been shown to up-regulate the cough reflex. Cavanaugh EJ, Simkin D, Kim D. Activation of transient receptor potential A1 channels by mustard oil, tetrahydrocannabinol and Ca2+ reveals different functional channel states. Primary afferent activation of thermosensitive TRPV1 triggers asynchronous glutamate release at central neurons. [14] This refractory cough is a common cause for stopping ACE inhibitor therapy. Plasticity of central mechanisms for cough. In addition, 12-HPETE has been also shown to activate TRPA1 via hepoxilins A3 and B3 formation [40]. Given that cough is predominantlyvagally mediated and that the same agents which enhance afferent vagal nerve activity also sensitize the cough reflex, the role of peripheral sensitization in cough is now well established [15]. 4b and c). In this study, using Group 1 was pretreated with the vehicle of the COX inhibitor (indomethacin). 1997;273(6 Pt 1):L113240. Cite this article. Thorax. * p<0.05, significant difference compared to vehicle/BK treated animals. A local accumulation of bradykinin may lead to activation of pro-inflammatory peptides (e.g. Therefore, such action, in the nTS, may result in increased activation of AVPNs and increased airway obstruction. J Pharmacol Exp Ther. Bradykinin was detected in the blood plasma of animals after the addition of venom extracted from the Bothrops jararaca (Brazilian lancehead snake), brought by Rosenfeld from the Butantan Institute. Cough and Penh were assessed during the citric acid challenge and for 10min thereafter. Effect of e-cigarette use on cough reflex sensitivity. PulmCrit This implies that increased PGE2 release can increase neuronal activity in the brain stem which may in turn affect the airway tone. Wang D, Wang P, Jiang J, Lv Q, Zeng X, Hong Y. Activation of mas oncogene-related G protein-coupled receptors inhibits neurochemical alterations in the spinal dorsal horn and dorsal root ganglia associated with inflammatory pain in rats. EPIDEMIOLOGY ACE inhibitors induce angioedema in 0.1 to 0.7 percent of recipients, with data suggesting a persistent and relatively constant risk over time [ 1-11 ]. Lee LY, Hsu CC, Lin YJ, Lin RL, Khosravi M. Interaction between TRPA1 and TRPV1: synergy on pulmonary sensory nerves. Eur J Pharmacol. {citation needed April 2019}, Currently, bradykinin inhibitors (antagonists) are being developed as potential therapies for hereditary angioedema. Bronchoconstriction due to the release of inflammatory mediators by bradykinin is considered to be the main reason for dry cough associated with ACE inhibitor use . Haxhiu MA, Chavez JC, Pichiule P, Erokwu B, Dreshaj IA. J Auton Nerv Syst. and enrofloxacin 0.25mg kg-1 (s.c.), once a day for 3 consecutive days. Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE. Taylor JA, Novack AH, Almquist JR, Rogers JE. Our data show that the combination treatment with indomethacin and baicalein reduced the BK enhanced cough response by 76% compared to 35 and 28%, respectively,with each drug administered alone. 1989;53(1):95101. In half of these patients, the ACE inhibitor has to be discontinued. Eur J Pharmacol. Effect of i.c.v. The link between TRPV1 and TRPA1 activation and increased airway obstruction is not clear, However, multimodal activation of TRPV1 channels trigger increased spontaneous glutamate release within the nTS [26, 56, 78]. Fifteen min after infusion of BK, all animals were exposed to aerosolized citric acid (0.2M) for 10min. Am J Physiol Lung Cell Mol Physiol. 8023, revised 1978). Recently, sensitization of the cough reflex has been identified as an important mechanism in chronic cough, where cough can result from low level stimulation by chemical, mechanical, or thermal stimuli [12, 22]. Natl Health Stat Report. Respir Res 20, 110 (2019). Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity. Treatment with JNJ-17203212, at only 3 but not 1 mole ml1, significantly inhibited the BK-enhancement of Penh following citric acid challenge by 77% (P<0.05; Fig. Yanaga F, Hirata M, Koga T. Evidence for coupling of bradykinin receptors to a guanine-nucleotide binding protein to stimulate arachidonate liberation in the osteoblast-like cell line, MC3T3-E1. 2016;357(3):6208. 2007;323(2):66574. Animal models of cough: literature review and presentation of a novel cigarette smoke-enhanced cough model in the Guinea-pig. This effect was inhibited following i.c.v. Khalid S, Murdoch R, Newlands A, Smart K, Kelsall A, Holt K, et al. 6a). Bradykinin and prostaglandins are the most frequently proposed causes of the cough, 4,5 and many studies using nonsteroidal anti-inflammatory drugs, such as sulindac infusion of drugs. At the end of the experiment, the guinea pigs were sacrificed by CO2 asphyxiation. Proc Natl Acad Sci U S A. Ann Intern Med. Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors. PubMed The kinin B1 and B2 receptors belong to G protein coupled receptor (GPCR) family. Pretreatment with HOE-140 also resulted in a dose-dependent decrease in the BK-enhancement of Penh following citric acid challenge (mean AUCSEM: 9.83.3 and 8.41.1 for 10 and 100 nmole ml1 HOE-140; respectively, compared to vehicle pretreated animals, 21.06.5; Fig. Groups 2 and 3 were pretreated with 30 and 80 nmole ml1 of indomethacin, respectively, and 15 min after the infusion of the antagonist or its vehicle, animals were treated with BK (0.06 nmole ml1). Minerva Anestesiol. 2011;89(1112):37887. Pulm Pharmacol Ther. Indeed, SP injected into the fourth ventricle has been shown to remarkablyincrease tracheal cholinergic tone [70]. cough Correspondence to Of relevance also is that i.c.v. 4a). However, whether BK can sensitize the cough reflex via a central mode of action is not well established. [18] Bradykinins have been implicated in cell proliferation and migration in gastric cancers,[19] and bradykinin antagonists have been investigated as anti-cancer agents. 2004;17(6):4537 discussion 469-470. An important finding in this study is that simultaneous blockade of TRPV1 and TRPA1 results in a synergistic inhibitory effect on cough and airway obstruction. Enter bradykinin: a compound that lowers your blood pressure, increases inflammation, worsens pain and itchiness, and might even feed a growing tumor. The incidence of dry cough in patients receiving ACEIs vary among individual ACEIs, and is the lowest with perindopril. Similar to the effects on cough, pretreatment with indomethacin inhibited the BK-enhanced airway obstruction indicating that COX metabolites are involved not only in the BK-enhanced cough but airway obstruction as well. J Pharmacol Exp Ther. Bujalska-Zadrozny M, de Corde A, Cegielska-Perun K, Gasinska E, Makulska-Nowak H. Dose-depending effect of intracerebroventricularly administered bradykinin on nociception in rats. The role of the medullary raphe nuclei in regulation of cholinergic outflow to the airways. Not so fast. 2001;933:15774. A role for TRPV1 in bradykinin-induced excitation of vagal airway afferent nerve terminals. Similarly, ML-351 pretreatment did not affect the BK-enhancement of Penh following citric acid challenge (mean AUCSEM: 24.65.8 and 30.47.9 vs 30.39.1 for 5 and 20 mole ml1 compared to vehicle pretreated animals, respectively; Fig. This review presents the current evidence on incidence and mechanisms of cough associated with ACEIs use, and proposes a practical approach for managing the same for optimal cardiovascu Together, these data suggest that TRPV1, and also TRPA1, channels may act as a signaling hub for stimuli that sensitize the cough reflex. The role of excitatory amino acids in airway reflex responses in anesthetized dogs. administration of PGE2 results in an increased c-Fos expression in several brain regions including the brainstem [72, 80]. Studies Rai G, Joshi N, Perry S, Yasgar A, Schultz L, Jung JE, et al. In this study, using a conscious guinea pig model of cough, we investigated 1): whether central administration of BK plays a role in the sensitization of the cough reflex and/or airway obstruction in response to citric acid inhalation and 2): the mechanisms by which BK may sensitize both cough and airway obstruction in response to citric acid inhalation.
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