Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0010200 (cough)
 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The successful introduction of angiotensin converting enzyme (ACE) inhibitors in the treatment of patients with essential hypertension or heart failure has increased interest in the (patho)physiological role of the renin-angiotensin system (RAS). ACE is not only involved in the formation of angiotensin II from angiotensin I, but also inactivates vasoactive substances such as bradykinin and substance P. Accumulation of these substances during treatment with ACE inhibitors may contribute to both their therapeutic action and certain adverse effects associated with their use, such as cough and angioneurotic oedema. Renin inhibitors offer an alternative approach to inhibit the RAS. The major advantage of these, still experimental, drugs is their high specificity for the RAS since angiotensinogen is the only known substrate of renin. The currently available renin inhibitors are pseudopeptides that are rapidly taken up by the liver and excreted in the bile. Consequently, these drugs are subjected to a considerable first pass effect which limits their oral bioavailability. Additionally, plasma elimination half-life times are short and the duration of action is limited. Despite these shortcomings, single oral or intravenous administration results in a 80 to 90% inhibition of plasma renin activity and a slight reduction in blood pressure in patients with hypertension. The extent of blood pressure reduction is dependent on the patient's salt balance. After 1 week of oral treatment with the renin inhibitor remikiren, the antihypertensive effect was reduced in salt-repleted hypertensive patients. Subsequent intravenous administration of the drug did not further affect blood pressure, indicating that it was not the first pass effect that was limiting the efficacy of remikiren.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical pharmacokinetics and efficacy of renin inhibitors. 758 99

Angiotensin-converting enzyme inhibitors (ACE inhibitors) have been shown to be effective in improving symptoms and survival in patients with systolic left ventricular dysfunction. Despite their proven benefits the use of ACE inhibitors is still limited in many parts of the western world. In part, the underutilization of ACE inhibitors is due to the occurrence of side effects such as cough, renal dysfunction and first dose hypotension. These side effects are in part due to ACE inhibitor-induced bradykinin formation. Blockade of the effects of angiotensin II can however also be achieved with an angiotensin II type I receptor blocking agent such as losartan. To determine the relative safety and effectiveness of ACE inhibitors compared to an angiotensin II type I receptor blocking agent the evaluation of losartan and the elderly trial (Elite) is comparing the ACE inhibitor captopril to the angiotensin II type I receptor blocking agent losartan in elderly patients. When used ACE inhibitors are often given in doses lower than those shown to be effective in reducing mortality in the major randomized trials. Several trials are currently under way comparing low to high doses of ACE inhibitors which should provide information on the need to achieve the doses used in the major mortality studies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Importance of angiotensin-converting enzyme inhibitors in myocardial infarction and congestive heart failure: implications for clinical practice. 761 6

An isolated perfused lung model was developed in which the mechanisms of regulation of sensory neuropeptide overflow and bronchoconstrictor responses evoked by antidromic vagal nerve stimulation or various irritants could be studied. For further comparison, non-adrenergic non-cholinergic (NANC) bronchoconstriction was also studied in guinea-pig isolated bronchus and in vivo. In the isolated guinea-pig lung, spontaneous strong postmortem bronchoconstriction occurred; this had to be overcome by the beta 2-adrenoceptor agonist terbutaline. Vagal stimulation, capsaicin, resiniferatoxin (RTX), nicotine, and pH 5 buffer all caused sensory peptide release and bronchoconstriction via a capsaicin-sensitive mechanism. Bradykinin and histamine also stimulated sensory peptide release but evoked bronchoconstriction mainly via capsaicin-resistant mechanisms. Stimulation at low frequency (1 Hz) caused similar degree of sensory nerve activation (peptide release in perfused lung and NANC bronchial contraction in bronchus) as stimulation at 10 Hz. Dactinomycin and the non-peptide SR 48968 selectively blocked the bronchoconstriction induced by neurokinin 2 (NK2) receptor agonists and also depressed that induced either by vagal stimulation or capsaicin, with no prejunctional effect on the overflow of calcitonin gene-related peptide (CGRP). Furthermore, SR 48968 inhibited the bronchoconstriction to citric acid aerosol. The NK1 antagonist CP 96345 had only marginal effects on NANC bronchoconstriction. Tetrodotoxin (TTX) and omega-conotoxin (CTX) inhibited neuropeptide release and bronchoconstriction caused by vagal stimulation or a low concentration of capsaicin but only marginally attenuated the effects evoked by a high concentration of capsaicin, or nicotine. Prejunctional alpha 2-adrenoceptor or opiate receptor activation inhibited the neuropeptide release and bronchoconstriction induced by vagal stimulation or a low concentration of capsaicin. Ruthenium red had a selective inhibitory effect on the overflow of neuropeptides [CGRP, neurokinin A (NKA)] and bronchoconstriction induced by capsaicin and its analogue RTX but not on responses induced by vagal stimulation, nicotine, bradykinin and histamine. It also inhibited CGRP and NKA release and bronchoconstriction caused by pH 5 buffer in lung, as well as cough and nasal irritation provoked by citric acid in vivo. The capsaicin receptor antagonist capsazepine inhibited peptide (CGRP, NKA) release and bronchoconstriction produced by capsaicin but not that evoked by vagal stimulation, nicotine and bradykinin, suggesting selectivity. Citric acid (in vivo) and pH 5 buffer (in vitro) produced bronchoconstriction via activation of capsaicin-sensitive sensory nerves. Interestingly, capsazepine also markedly depressed peptide overflow and bronchoconstriction caused by pH 5 buffer in isolated guinea-pig lung.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of neuropeptide release from pulmonary capsaicin-sensitive afferents in relation to bronchoconstriction. 769 42

Bradykinin and related kinins are peptidic hormones, formed in tissues and fluids during inflammation. Various functional sites have been proposed as mediators of the biological effects of kinins, including the B1, B2 and B3 receptors. The existence of the B1 and the B2 receptor has largely been confirmed, whilst that of the B3 receptor is controversial and needs further confirmation. The role of bradykinin in the pathophysiology of asthma is not well understood, but bradykinin was proposed as a putative mediator of asthma, since asthmatic subjects are hyperresponsive to bradykinin, and since immunoreactive kinins are increased in the bronchoalveolar lavage fluids of asthmatic patients. Kinins could provoke bronchoconstriction by acting directly on smooth muscle and/or indirectly by their inflammatory properties. They may also contribute to the symptomatology of allergic and viral rhinitis, since they are the only mediators detected to date that are generated in nasal secretion during experimental and natural rhinovirus colds. Moreover, they can induce relevant symptoms when applied to airway mucosa. It has also been proposed that coughing during treatment with angiotensin-converting enzyme (ACE) inhibitors is linked to the action of kinins, since ACE is able to degrade kinins, and since the effects of ACE inhibitors are reduced by kinin antagonists. Due to their mitogenic properties, kinins have been proposed to regulate lung carcinoma growth. Their action remains speculative, but some findings are of great interest in order to define their role in these pathologies. Despite many studies in animals and in humans, the mode of action of kinins in airways is still poorly understood.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kinins and respiratory tract diseases. 838 34

There is increasing evidence that the sensory nerves of the airway play a role in the asthmatic response. Nerve endings are exposed by the epithelial shedding that occurs with asthma. They may become sensitized and activated by inflammatory mediators and may release neuropeptides that then spread and amplify the inflammatory process in the airways. Nedocromil sodium may prevent the sensory nerves from becoming sensitized and inhibit their activation. This possibility is suggested because nedocromil is highly effective against several indirect challenges that involve sensory nerve stimulation. Nedocromil sodium was able to inhibit the bronchoconstriction induced in patients with asthma by exposure to bradykinin, sulfur dioxide, metabisulfite, and ultrasonically nebulized water. Cough, which is a prominent symptom of asthma, is believed to be a result of sensory nerve activation. In several long-term clinical studies, nedocromil sodium reduces the severity of cough among patients with asthma. Studies are needed to define how nedocromil sodium acts on the sensory nerves.
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PMID:Effect of nedocromil sodium on airway sensory nerves. 839 25

We investigated the effect of imidapril, a novel angiotensin-converting enzyme (ACE) inhibitor, on augmentation of airway microvascular leakage induced by bradykinin (BK) and substance P (SP) in guinea pigs and compared it with those of enalapril and captopril. The three ACE inhibitors significantly potentiated BK- and SP-induced airway microvascular leakage in a dose-dependent manner. In spite of the compatible or higher ACE inhibitory activity of imidapril, its potentiating activity in BK-induced leakage was lower than those of enalapril and captopril both by single administration (0.3-30 mg/kg, p.o.) and repeated administration for eight days (0.1-10 mg/kg/day, p.o.). The potentiating activities of the three ACE inhibitors were suppressed by pretreatment with a BK2-receptor antagonist, but not by neurokinin 1 and neurokinin 2 antagonists, suggesting that neurokinins may not be involved in BK-induced leakage under the conditions used. On the other hand, the potentiating effect of imidapril in SP-induced leakage was weaker than those of enalapril and captopril only after single high doses. The present study shows that the ACE inhibitors have different activity in potentiation of the airway microvascular leakage induced by BK, which may be ascribable to the difference in their inhibition of BK hydrolysis. This evidence may partly explain the smaller incidence of dry cough induced by imidapril compared with other ACE inhibitors when clinically used as antihypertensive drugs.
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PMID:Difference among angiotensin-converting enzyme inhibitors in potentiating effects on bradykinin-induced microvascular leakage in guinea pig airways. 856 47

Angiotensin-converting enzyme inhibitors (ACE-I) have been proven to be effective in reducing morbidity and mortality in patients with heart failure or post-myocardial infarction left ventricular dysfunction. Despite evidence from several large-scale randomized trials, the use of ACE-I in patients with heart failure remains relatively low. In part, the failure to achieve more widespread use of ACE-I in patients with heart failure may be due to physician's perceptions of the side effects associated with ACE-I, such as angioedema, renal dysfunction, cough, and hypotension. Many of these side effects are thought to be due to ACE-I-induced bradykinin accumulation. It is possible to inhibit the effect of angiotensin II without increasing bradykinin levels using an angiotensin II type I blocking agent such as losartan. How effective losartan is compared with an ACE-I is uncertain, however. Some of the beneficial effects of ACE-I have been attributed to bradykinin accumulation, and therefore ACE-I might have an advantage compared with an angiotensin II type I receptor antagonist such as losartan. On the other hand, angiotensin II may be produced by non-ACE-I-dependent mechanisms, which would suggest that an angiotensin II type I receptor blocking agent would be advantageous. To determine the relative safety and efficacy of an ACE-I, which results in bradykinin accumulation and inhibitors of angiotensin II, versus an angiotensin II type I receptor blocking agent, which does not result in bradykinin accumulation, we have begun the Evaluation of Losartan In The Elderly (ELITE) trial, which will compare the safety and efficacy of captopril and losartan in elderly patients with heart failure.
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PMID:Angiotensin II receptor antagonists in heart failure: rationale and design of the evaluation of losartan in the elderly (ELITE) trial. 857 52

The pharmacokinetics and pharmacodynamics of enalapril, an angiotensin converting enzyme inhibitor, are reported to vary with the time of administration. The present study was undertaken to examine whether the effect of enalapril on plasma bradykinin (BK), substance P and prostaglandin E2 (PGE2), which are likely to be involved in the mechanism of enalapril-induced cough, might also be affected by its time of administration. Enalapril 5 mg or placebo was given orally at 10:00 h (day trial) or 22:00 h (night trial) to 12 patients with essential hypertension. Serum concentrations of total drug (enalapril + enalaprilat, its active metabolite) during the day and night trials did not differ significantly at any time. However, serum enalaprilat tended to be higher and its maximum concentration greater in the day trial than in the night trial. Blood pressure 24 h after administration of enalapril was reduced at 22:00 h, but not at 10:00 h. Plasma BK tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. Remarkable increases in plasma BK were observed in two patients in the day trial and one of them also complained of cough. However, no such increase in plasma BK or subsequent adverse effect were recorded in the night trial. Plasma substance P and PGE2 did not change significantly following enalapril administration either in the day or night trial. The results suggest that the response of BK to enalapril is affected by the time of administration. In patients who complain of cough during treatment with enalapril during the daytime, this adverse effect might be diminished or eliminated by a switch to night-time administration.
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PMID:Chronopharmacology of enalapril in hypertensive patients. 858 61

The past few decades have seen a remarkable development in the field of pharmacological therapy, one of the most notable examples being the treatment of arterial hypertension. Some of the early anti-hypertensive agents were relatively crude by today's standards, but gradually efficacy, tolerability, or both, of blood pressure-lowering (BP) drugs have been improved. It is presently possible to choose from a number of effective and well-tolerated compounds for the treatment of hypertension. The latest additions to the anti-hypertensive armamentarium are the angiotensin II receptor antagonists, the most advanced of these being losartan. It is perhaps most relevant to compare losartan to the angiotensin converting enzyme (ACE) inhibitors, another class of anti-hypertensive agents which acts mainly by interfering with the renin-angiotensin-aldosterone system (RAAS). Studies have shown that losartan lowers BP at least as effectively as ACE inhibitors. However, the side-effect profile of losartan is more favourable. In particular cough, a relatively common side-effect of ACE inhibitors, has been shown to be significantly less common during losartan treatment. This is probably because losartan does not interfere with bradykinin metabolism, unlike the ACE inhibitors. Regarding the reversal of left ventricular hypertrophy (LVH), a powerful risk indicator for cardiovascular disease, we have shown that losartan is more effective in this regard than treatment with the beta-blocker atenolol. It appears, based on these and other findings, that interference with the RAAS is particularly useful in causing reversal of the cardiovascular hypertrophic changes. The prognostic implications remain to be demonstrated, but it would be logical to expect a benefit from this effect. It was recently shown that polymorphism of the ACE gene is associated with increased risk of coronary heart disease even in the absence of conventional risk factors. If these findings are confirmed the interest in interfering with the RAAS as a therapeutic modality in hypertension would obviously be strengthened. It is not easy to predict the future role of any new therapeutic modality. The positive relation between efficacy and tolerability of losartan, as well as the fact that several observations suggest that interference with the RAAS could be favourable from a prognostic point of view, suggest that losartan may come to play an important role in the future treatment of hypertension.
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PMID:The future role of losartan. 858 83

Angiotensin converting enzyme (ACE) -inhibitors inhibit degradation of inflammatory mediators substance P (SP) and bradykinin, which may further stimulate the synthesis of prostaglandins. The resulting increase in inflammatory mediators in tissues is suggested to be the reason for the dry cough, involving sensory C-fiber activation, among patients receiving ACE-inhibitor therapy. In the present study, the effect of an ACE-inhibitor, captopril, on ocular irritative responses was studied in the rabbit. Intravenous captopril decreased markedly the blood pressure and the intraocular pressure (IOP) modestly. Topical neutral formaldehyde elicits an irritative response in the eye mediated through sensory neuropeptides SP and calcitonin gene-related peptide (CGRP). Following topical neutral formaldehyde, the increase in IOP and breakdown of the blood-aqueous barrier were inhibited by captopril, while miosis was not affected. Cyclic AMP (cAMP) content in the aqueous humour was increased by captopril, and this increase was inhibited by indomethacin. Following YAG-laser anterior capsulotomy, captopril inhibited the increase in IOP, breakdown of the blood-aqueous barrier and miosis. The present study demonstrates that use of short-term administration of captopril prior to sensory nerve stimulation or YAG laser anterior capsulotomy does not enhance the ocular responses to these stimuli in the rabbit. In the present study, captopril inhibited these responses, at least partly by decreasing the blood pressure.
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PMID:Effect of captopril on ocular irritative response to topical neutral formaldehyde and YAG-laser capsulotomy in the rabbit. 859 Feb 56


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