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Query: UMLS:C0010200 (cough)
 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Whether any class of antihypertensive drugs has specific renoprotective effects above and beyond lowering of blood pressure is still debatable. The renin-angiotensin system (RAS) is both localized and has many actions within the kidney, on intrarenal hemodynamics, on the mesangial cell, as well as stimulating growth factors and cytokines. Angiotensin converting enzyme (ACE) inhibitors have been shown to ameliorate the progression of renal failure. How much of this beneficial effect is due to their hemodynamic effects, how much to non-hemodynamic effects and how much to their effects on bradykinin and other putative ACE substrates is still unclear. Experimentally it can be shown that inhibiting ACE but preventing the fall in systemic blood pressure by salt loading abolishes renoprotection. Bradykinin has been implicated in both the beneficial and the adverse effects of ACE inhibitors. Because of this and because ACE inhibitors may not provide complete blockade of the RAS, angiotensin receptor (AT1R) antagonists have been developed. Experimentally AT1R antagonists have been shown to reproduce most of the beneficial effects of ACE inhibitors. The experience in humans is more limited but they have been demonstrated to be efficacious in hypertension, to reduce proteinuria, and produce a favorable hemodynamic effect in congestive cardiac failure with a low incidence of adverse effects and without cough. Calcium channel blockers (CCB) also have additional properties that may provide renoprotection beyond lowering blood pressure. However, as the different types of CCB block different calcium channels their effects may differ substantially. The inconsistency of the data in the renoprotective effect of CCB may reflect these differences. Quantitatively probably the most important factor in preventing the progress of renal failure by antihypertensive drugs is strict control of blood pressure. Lowering blood pressure by drugs is most likely effective by both reducing physical and sheer stress damage, as well as turning off the signal for the activation and production of vasoactive peptides and cytokines.
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PMID:Comparison of renin-angiotensin to calcium channel blockade in renal disease. 940 14

Hypertension is a major problem throughout the developed world. Although current antihypertensive treatment regimens reduce morbidity and mortality, patients are often noncompliant, and medications may not completely normalize blood pressure. As a result, current therapy frequently does not prevent or reverse the cardiovascular remodeling that often occurs when blood pressure is chronically elevated. Blockade of the renin-angiotensin system (RAS) is effective in controlling hypertension and treating congestive heart failure. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) inhibit the activity of the RAS, but these two classes of antihypertensive medications have different mechanisms of action and different pharmacologic profiles. Angiotensin-converting enzyme inhibitors block a single pathway in the production of angiotensin II (Ang II). In addition, angiotensin I is not the only substrate for ACE. The ACE inhibitors also block the degradation of bradykinin that may have potential benefits in cardiovascular disease. Bradykinin is, however, the presumed cause of cough associated with ACE inhibitor therapy. Data from clinical trials on ACE inhibitors serve to support the involvement of the RAS in the development of cardiovascular disease. Angiotensin receptor blockers act distally in the RAS to block the Ang II type 1 (AT1) receptor selectively. Thus, ARBs are more specific agents and avoid many side effects. Experimental and clinical trials have documented the efficacy of ARBs in preserving target-organ function and reversing cardiovascular remodeling. In some instances, maximal benefit may be obtained with Ang II blockade using both ARBs and ACE inhibitors. This review describes clinical trials that document the efficacy of ARBs in protecting the myocardium, blood vessels, and renal vasculature.
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PMID:Angiotensin receptor blockers: evidence for preserving target organs. 1128 62

Chronic exposure to irritants such as tobacco smoke (TS) can induce spontaneous and enhanced irritant-induced coughing, especially in asthma. To determine if the mechanism of enhanced coughing involves activation of capsaicin-sensitive sensory receptors (C-fibers), we exposed both non-sensitized (NS) and ovalbumin-sensitized guinea pigs to TS (5 mg/L air, 30 min exposure, and 7 days/week). Similar groups were exposed to compressed air. After 90 days of exposure, we challenged the airways with capsaicin, bradykinin, histamine and methacholine. Capsaicin induced coughing as well as bronchoconstriction in guinea pigs exposed to TS. In ovalbumin (OA) guinea pigs coughing and bronchoconstriction were enhanced. Tachykinin receptor antagonists attenuated coughing to both capsaicin and acute TS challenge. Bradykinin also induced coughing and bronchoconstriction in guinea pigs exposed to TS. There was no statistical separation between the two TS groups however. Histamine and methacholine induced similar bronchoconstriction but fewer coughs in all four experimental groups. In conclusion, chronic TS exposure induced coughing to capsaicin and bradykinin challenge. The effect of capsaicin was further enhanced in OA guinea pigs. Enhanced coughing induced by TS exposure likely involves activation of capsaicin-sensitive sensory C-fibers and neuropeptide release with possible subsequent activation of rapidly-adapting receptors.
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PMID:Chronic tobacco smoke exposure increases cough to capsaicin in awake guinea pigs. 1134 40

Plasma exudation has been suggested to be an important component of the inflammatory response in asthma. Bradykinin elicits many of the features of asthma, including bronchoconstriction, cough, plasma exudation and mucus secretion. In an attempt to quantify local plasma exudation, we have employed a novel low-trauma technique with the aim of challenging and lavaging a central part of the bronchial tree, by selecting a medium sized bronchus. A fibreoptic bronchoscopy was performed in non-smoking healthy volunteers. The instrument was placed proximally in the right upper lobe bronchus. A plastic catheter, equipped with an inflatable latex balloon, was inflated with air (2-4 cmH2O). A solution (100 microl of either two different concentrations of bradykinin: 0.09 and 0.9 mg ml(-1) or normal saline) was instilled through the catheter and distal to the balloon. Eight minutes later a lavage procedure with 10 ml of saline was performed through the catheter. The procedure was then repeated twice, with the other solutions, but from the lingular and middle lobe bronchi. All solutions were given in a blinded fashion, and two different studies were performed. Lavage concentrations of albumin and IgG were quantified as measurements of plasma exudation. In our first study we found that bradykinin challenge significantly increased concentrations of albumin and IgG. In study two, there was no numeric increase in plasma proteins after local bradykinin challenge, but the concentration of thromboxane was significantly increased in lavages from bradykinin-challenged bronchi. Thus, local bronchial administration of bradykinin has the capacity to induce exudation of large plasma macromolecules into the bronchial lumen, as well as local thromboxane production.
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PMID:Exudation of plasma and production of thromboxane in human bronchi after local bradykinin challenge. 1139 69

Angiotensin-converting enzyme (ACE) inhibitors are among the first-choice drugs for treating hypertension and congestive heart disease. It has been reported, however, that these drugs could induce chronic cough and airway hyperresponsiveness. The aim of this work was to assess in pigs the effects of bradykinin and tachykinins on citric-acid-induced coughing after ACE inhibitor pretreatment. Coughing was induced by challenging pigs with an aerosol of 0.8 M citric acid over 15 min. Coughs were counted by a trained observer for 30 min. The animals underwent two cough induction tests two days apart (days 1 and 3), the first being taken as a control. All drugs were injected intravenously 30 min before the second challenge. In the control group, no difference was observed between days 1 and 3. The ACE inhibitor enalapril (7.5 and 15 microg/kg) caused the cough frequency to increase significantly. In contrast, a dose-related decrease was observed with Hoe140 (icatibant), a bradykinin B2 receptor antagonist (0.5 and 1 mg/kg). When both drugs were administered simultaneously (15 microg/kg for enalapril and 1 mg/kg for Hoe140), a significant increase was observed as compared with the control value obtained on day 1. When enalapril was combined with the three tachykinin receptor antagonists SR 140333 (NK1 receptor antagonist), SR 48968 (NK2 receptor antagonist) and SR 142801 (NK3 receptor antagonist), a significant decrease was observed as compared with control value obtained on day 1; the percentage of variation was also significantly different as compared with those observed in enalapril groups at both doses. These data suggest that ACE-inhibitor-induced enhancement of the cough reflex is mainly due to tachykinins and not to bradykinin in our pig model. Bradykinin, however, plays a major role in coughing induced by citric acid alone.
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PMID:Role of bradykinin and tachykinins in the potentiation by enalapril of coughing induced by citric acid in pigs. 1146 10

Bradykinin (BK) and related kinins are autocoid peptides that play integral roles in many pathophysiological processes such as cough. In this study, the inhibitory effect of noscapine, the antitussive opioid alkaloid, on BK receptors, was tested in the guinea-pig ileum. Contractions of the isolated ileum of the guinea-pig in response to BK were inhibited by noscapine (10-1,000 nM) in a concentration-dependent manner. Concentration-response curves (CRCs) to BK were slightly shifted to the right with a concomitant decrease in the maximum effect. A pA2 value of 6.68 was calculated for noscapine. The slope of the Schild plot of the antagonism was found to be 0.56. Noscapine had no effect on contractions induced by KCl, acetylcholine, histamine, 5-hydroxy tryptamine or angiotensin II. In conclusion, noscapine has a specific antagonistic effect on BK receptors and the mode of inhibition was found to be non-competitive.
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PMID:Efffect of noscapine, the antitussive opioid alkaloid, on bradykinin-induced smooth muscle contraction in the isolated ileum of the guinea-pig. 1216 81

1. Bradykinin (BK) is a nine amino acid peptide (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) formed from the plasma precursor kininogen during inflammation and tissue injury. The actions of BK are mediated by G protein-coupled cell surface receptors, designated B1 and B2. 2. BK has a plethora of effects in the airways including bronchoconstriction, bronchodilation, stimulation of cholinergic and sensory nerves, mucus secretion, cough and oedema resulting from promotion of microvascular leakage. These airway effects are mediated in the main by the B2 receptor subtype. 3. BK acts mainly indirectly, primarily through airway nerve activation, but also by the release of prostanoids, thromboxanes and nitric oxide (NO). 4. Airway responses to BK have been studied in detail in guinea-pigs, mice, sheep and rats. This review describes the effects of BK in these species and draws comparison with its effects in normal humans and patients with respiratory diseases. 5. Despite its many and varied effects in the airways of animals and man, the exact contribution of BK to airways disease remains unclear.
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PMID:Species differences in bradykinin receptor-mediated responses of the airways. 1242 22

We have identified the tracheal and laryngeal afferent nerves regulating cough in anaesthetized guinea-pigs. Cough was evoked by electrical or mechanical stimulation of the tracheal or laryngeal mucosa, or by citric acid applied topically to the trachea or larynx. By contrast, neither capsaicin nor bradykinin challenges to the trachea or larynx evoked cough. Bradykinin and histamine administered intravenously also failed to evoke cough. Electrophysiological studies revealed that the majority of capsaicin-sensitive afferent neurones (both Adelta- and C-fibres) innervating the rostral trachea and larynx have their cell bodies in the jugular ganglia and project to the airways via the superior laryngeal nerves. Capsaicin-insensitive afferent neurones with cell bodies in the nodose ganglia projected to the rostral trachea and larynx via the recurrent laryngeal nerves. Severing the recurrent nerves abolished coughing evoked from the trachea and larynx whereas severing the superior laryngeal nerves was without effect on coughing. The data indicate that the tracheal and laryngeal afferent neurones regulating cough are polymodal Adelta-fibres that arise from the nodose ganglia. These afferent neurones are activated by punctate mechanical stimulation and acid but are unresponsive to capsaicin, bradykinin, smooth muscle contraction, longitudinal or transverse stretching of the airways, or distension. Comparing these physiological properties with those of intrapulmonary mechanoreceptors indicates that the afferent neurones mediating cough are quite distinct from the well-defined rapidly and slowly adapting stretch receptors innervating the airways and lungs. We propose that these airway afferent neurones represent a distinct subtype and that their primary function is regulation of the cough reflex.
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PMID:Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. 1500 8

It has been reported that the incidence of angiotensin-converting enzyme (ACE) inhibitor-related dry cough is significantly less with the ACE inhibitor imidapril than with the ACE inhibitor enalapril in hypertensive patients. Bradykinin (BK) in the trachea is believed to play some role in this adverse effect. The present study was undertaken to evaluate the effects of imidapril and enalapril on the activity of aminopeptidase P (APP), one of the BK-metabolizing enzymes, in the mouse trachea. Imidapril (0.5 mg/kg) or enalapril (0.5 mg/ kg) was given orally to mice once daily for 7 days. Drug concentrations and APP activity in the trachea were determined at the end of the experiment. Active metabolites (imidaprilat and enalaprilat), but not parent drugs (imidapril and enalapril) were detected in the trachea after a repeated dose for 7 days. Tissue concentrations of imidaprilat and enalaprilat did not significantly differ. The APP activity in the trachea did not significantly change after the 7th dose of imidapril. However, the enzyme activity was significantly inhibited after the final dose of enalapril. Thus, the present study showed that enalapril, but not imidapril inhibited the airway APP activity during repeated dosing. This finding is compatible with previous reports that the incidence of dry cough is lower with imidapril than with enalapril, and with the hypothesis that the dry cough induced by ACE inhibitors may be related to accumulation of BK in the trachea.
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PMID:Different effects of imidapril and enalapril on aminopeptidase P activity in the mouse trachea. 1609 68

Bradykinin has been implicated as a mediator of the acute pathophysiological and inflammatory consequences of respiratory tract infections and in exacerbations of chronic diseases such as asthma. Bradykinin may also be a trigger for the coughing associated with these and other conditions. We have thus set out to evaluate the pharmacology of bradykinin-evoked coughing in guinea pigs. When inhaled, bradykinin induced paroxysmal coughing that was abolished by the bradykinin B2 receptor antagonist HOE 140. These cough responses rapidly desensitized, consistent with reports of B2 receptor desensitization. Bradykinin-evoked cough was potentiated by inhibition of both neutral endopeptidase and angiotensin-converting enzyme (with thiorphan and captopril, respectively), but was largely unaffected by muscarinic or thromboxane receptor blockade (atropine and ICI 192605), cyclooxygenase, or nitric oxide synthase inhibition (meclofenamic acid and N(G)-nitro-L-arginine). Calcium influx studies in bronchopulmonary vagal afferent neurons dissociated from vagal sensory ganglia indicated that the tachykinin-containing C-fibers arising from the jugular ganglia mediate bradykinin-evoked coughing. Also implicating the jugular C-fibers was the observation that simultaneous blockade of neurokinin2 (NK2; SR48968) and NK3 (SR142801 or SB223412) receptors nearly abolished the bradykinin-evoked cough responses. The data suggest that bradykinin induces coughing in guinea pigs by activating B2 receptors on bronchopulmonary C-fibers. We speculate that therapeutics targeting the actions of bradykinin may prove useful in the treatment of cough.
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PMID:Pharmacology of Bradykinin-Evoked Coughing in Guinea Pigs. 2700 Aug 1


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