Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:7440-70-2 (calcium)
 333,191 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that N/OFQ, the endogenous peptide ligand for the 'opioid-like' NOP receptor, inhibits cough in guinea pigs and cats. In the present study we sought to continue our characterization of the cough-suppressant effects of NOP stimulation by profiling the pulmonary and antitussive effects of a novel non-peptide NOP agonist, Ro-64-6198, in guinea pigs. In receptor-binding assays, we confirmed that Ro-64-6198 selectively binds to NOP receptors over other opioid receptors. The Ki values for Ro-64-6198 at NOP, MOP, KOP and DOP receptors was 0.3, 36, 214 and 3,787 nmol/l, respectively. In GTPgammaS-binding assays, Ro-64-6198 displayed >900-fold functional selectivity at NOP relative to MOP receptors. We evaluated the effects of Ro-64-6198 (3 and 10 micromol/l) in isolated guinea pig nodose ganglia cells on the increases in intracellular Ca2+ concentration evoked by capsaicin stimulation (1 x 10(-8)-1 x 10(-6) mol/l). Similar to previously reported data with N/OFQ, Ro-64-6198 (3 and 10 micromol/l) significantly attenuated Ca2+ responses in nodose ganglia cells produced by exposure to capsaicin. The effect of Ro-64-6198 (3 micromol/l) on capsaicin-induced intracellular Ca2+ responses was blocked by the NOP antagonist, J113397 (3 micromol/l). In guinea pig in vivo studies, aerosolized capsaicin (10-300 micromol/l) produced a dose-dependent increase in cough number. Ro-64-6198 given i.p. significantly inhibited cough due to capsaicin (300 micromol/l) exposure. In a duration study we found that the maximum antitussive effect (42 +/- 8% inhibition) of Ro-64-6198 (3 mg/kg) was observed at 1 h after i.p. administration. Also at 1 h after administration, Ro-64-6198 (0.003-3.0 mg/kg, i.p.) produced a dose-dependent inhibition of cough. The antitussive effect of Ro-64-6198 (3 mg/kg, i.p.) was blocked by J113397 (12 mg/kg, i.p.) but not by the classical opioid antagonist naltrexone (10 mg/kg, i.p.). Although the antitussive action of Ro-64-6198 may be mediated by a central and/or a peripheral site of action, we hypothesize that selective oral NOP agonists that do not penetrate the blood-brain barrier may provide a novel approach for the treatment of cough. Moreover, because these drugs do not interact at MOP receptors, they may be devoid of codeine-like side effects such as respiratory depression, sedation, constipation or proclivities for addictive liabilities.
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PMID:Antitussive profile of the NOP agonist Ro-64-6198 in the guinea pig. 1516 96

All currently available antihypertensive drugs can cause adverse drug reactions. Potential adverse drug reactions should already be taken into account when a new antihypertensive regimen is started. It is furthermore important to ask at follow-up visits specifically about common adverse reactions. The aims of this article are therefore to shortly summarise common and typical adverse drug reactions of antihypertensives. All antihypertensives may cause dizziness, hypotension, allergies, rashes, gastrointestinal complaints and dry mouth. Thiazide diuretics furthermore may cause electrolyte disturbances, dehydration and hyperuricemia, betablockers may cause bronchospasm, bradycardia, cold extremities and sleep disturbances and calcium antagonists may cause flushing, ankle oedema and gingival hyperplasia. Concerning potential lethal adverse drug reactions, it is important to know that ACE inhibitors and angiotensin receptor antagonists are contraindicated in all patients with a history of angioedema. However, angiotensin receptor antagonists are well-suited alternatives for patients with ACE inhibitor-induced cough or hypogeusia. Rare adverse drug reactions are commonly recognised only after drug approval based on spontaneous reporting. This demonstrates the importance of considering medications as potential causes of new complaints and symptoms and to reports such suspected adverse drug reactions to the national pharmacovigilance centres. Only the local or international accumulation of comparable spontaneous reports allows the drug regulation agencies to recognise new and unexpected adverse drug reactions early and to initiate appropriate measures.
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PMID:[Antihypertensives--which adverse drug reactions are clinically relevant?]. 1519 39

N-alpha-Tosyl l-arginine methyl ester [TAME]-esterase appears to be an important biochemical marker, which displays potent contractile properties on bronchial tissues and aorta in vitro. TAME-esterase induced contractions have been shown to be mediated via a nitric oxide-cyclic GMP pathway. TAME-esterase has also been described to be a possible new cardiovascular risk factor among smokers. TAME-esterase has been reported to be an enzyme, which is involved during the sequence of events leading to the activation of the kinin-kallikrein system. Use of aprotinin (a kallikrein inhibitor) as well as aspirin and indomethacin (prostaglandin inhibitors) have shown that there is an inter-dependent relationship between the kinin-kallikrein system and the cyclo-oxygenase pathway involved during the sequence of reactions leading to TAME-esterase induced contractions. Our findings also lend support to the concept of calcium antagonism whereby verapamil, and nifedipine, mimicked in reversible fashion the effects of Ca2+ withdrawal on muscle excitability during TAME-esterase induced contractions on rat aorta in vitro. We concluded that the effects of captopril, an ACE inhibitor, on TAME-esterase induced contractions could thus be due to the degradation of bradykinin by the enzyme kininase being blocked. This paper proposes an integrated model of possible biochemical-pharmacological pathways, which involve events leading to TAME-esterase induced contractions. We hypothesize that TAME-esterase induced cough through sensitization of airway sensor nerves in hypertensive patients taking angiotensin-converting enzyme inhibitors can be inhibited by aprotinin.
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PMID:Aprotinin suppresses ACE-inhibitor cough triggered by TAME-esterase. 1532 12

There are several receptors capable of inducing activating generator potentials in cough-associated afferent terminals in the airways. The chemical receptors leading to generator potentials can be subclassified into ionotropic and metabotropic types. An ionotropic receptor has an agonist-binding domain, and also serves directly as an ion channel that is opened upon binding of the agonist. Examples of ionotropic receptors found in airway sensory nerve terminals include receptors for serotonin (5-HT3 receptors), ATP (P2X receptors), acetylcholine (nicotinic receptors), receptors for capsaicin and related vanilloids (TRPV1 receptors), and acid receptors (acid sensing ion channels). Afferent nerve terminals can also be depolarized via activation of metabotropic or G-protein coupled receptors (GPCRs). Among the GPCRs that can lead to activation of airway afferent fibers include bradykinin B2 and adenosine A1 receptors. The signaling events leading to GPCR-mediated membrane depolarization are more complex than that seen with ionotropic receptors. The GPCR-mediated effects are thought to occur through classical second messenger systems such as activation of phospholipase C. This may lead to membrane depolarization through interaction with specific ionotropic receptors (such as TRPV1) and/or various types of calcium activated channels.
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PMID:Ionotropic and metabotropic receptor mediated airway sensory nerve activation. 1556 76

Cough is an important defensive reflex of the airway and also a common symptom of respiratory disease. Cough after common respiratory virus infection is transient but is more persistent when associated with conditions such as asthma, rhinosinusitis, gastro-oesophageal reflux, chronic obstructive pulmonary disease and lung cancer. Persistent cough may be due to peripheral and/or central sensitisation of cough reflexes initiated by cough receptors, rapidly adapting receptors or nociceptors. Treatment directed at associated conditions such as asthma (with anti-inflammatories) and gastro-oesophageal reflux (with proton-pump inhibitors) improve cough. There remains a need to use drugs that suppress the neural activity of cough (termed nonspecific), as treatments directed at the clinical cause(s) of the underlying cough (termed specific) may not be effective. The most effective indirect antitussives are opioids such as morphine, codeine or pholcodeine, but they produce side effects such as drowsiness, nausea, constipation and physical dependence. Opioids such as kappa- and delta-receptor agonists, non-opioids such as nociceptin, neurokinin and bradykinin receptor antagonists, cannabinoids, vanilloid receptor-1 antagonists, blockers of Na+-dependent channels, and large conductance Ca2+-dependent K+-channel activators of afferent nerves may represent novel antitussives.
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PMID:Drugs to suppress cough. 1570 18

Metastatic pulmonary calcification (MPC) characterized by diffuse calcium deposition in the lungs is known to occur in patients with chronic renal failure. However, MPC with pulmonary artery calcification is uncommon and has only been detected in a few patients with severe disorders. A 48-year-old man with chronic renal failure had cough and progressive dyspnea. Ventilation-perfusion (V/Q) lung scans showed multiple large-sized mismatched V/Q defects in the left middle and lower zones of lungs, which was consistent with a high probability of pulmonary embolism (PE). The findings of pulmonary scintigraphy resulted from MPC with pulmonary artery calcification, revealed by simultaneous technetium-99m MDP scintigraphy, low-dose computed tomography, and high-resolution computed tomography (HRCT) of the chest.
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PMID:Metastatic pulmonary calcification in renal failure mimicking pulmonary embolism on lung scan. 1582

TRPV1 is a modulator of noxious stimuli known to be important in the cough reflex. We have compared the expression of TRPV1 in normal human airways and those from patients with chronic cough and found that there is up regulation in airways smooth muscle in disease. This increased expression appears to be intracellular and we have therefore examined the role of intracellular rat and human TRPV1 activity was found using intracellular calcium signalling with human intracellular TRPV1 being located in a thapsigargin insensitive compartment. Increase in TRPV1 activity may have a role in the airway hypersensitivity seen in chronic cough.
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PMID:Expression and characterization of the intracellular vanilloid receptor (TRPV1) in bronchi from patients with chronic cough. 1596 10

Valsartan is the second orally-active, non-peptide angiotensin II receptor blocker to reach the market in Europe and the USA for the treatment of hypertension. Preclinical studies have demonstrated that this blocker is specific for the AT(1) receptor and has no affinity for the angiotensin II AT(2) receptor. Experimentally, valsartan dose-dependently inhibits the vasoconstriction induced by angiotensin II and lowers blood pressure in renin-dependent models of hypertension. Pharmacologically, oral valsartan is characterised by a low bioavailability but a rapid absorption and distribution with a half-life in keeping with once-daily administration. Thus, after oral administration, the maximal plasma concentration is reached 2 h after dosing and the elimination half-life is about 6 h. Clinically, several dose-finding and comparative studies have demonstrated that valsartan is an effective and well-tolerated antihypertensive drug in patients with mild to moderate hypertension. Valsartan has also been shown to be effective in severe hypertension. Valsartan is at least as effective as ACE inhibitors, diuretics, beta-blockers and calcium antagonists. However, none of the side-effects observed with these latter agents, including cough and lower limb oedema, has been observed with the administration of valsartan. Three large clinical trials are now underway to demonstrate whether valsartan can reduce morbidity and mortality: one in hypertensives with a high cardiovascular risk profile (VALUE), one in patients with heart failure previously treated with an angiotensin-converting enzyme inhibitor (VAL-HeFT) and one in post-myocardial infarct patients (VALIANT). These studies will further define the place of valsartan beyond the treatment of hypertension.
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PMID:Pharmacology of valsartan, an angiotensin II receptor antagonist. 1599 38

It has been reported that star fruit can lead to a fatal outcome in uremic patients. The intoxication syndrome consists of hiccups, mental confusion, dizziness, and vomiting. On the other hand, folk medicine uses teas and infusions of carambola leaves to treat headache, vomiting, cough, insomnia, and diabetes. This motivated us to determine if Averrhoa carambola can act on the contractility and automaticity of the guinea pig heart. We measured the atrial isometric force in stimulated left atria and determined the chronotropic changes in spontaneously beating right atria. The carambola leaf extracts (1.5 mg/ml) abolished the contractile force in a concentration-dependent manner. Among the crude, methanolic, ethanolic, aqueous, and acetic extracts, the aqueous one was the most potent (EC50 = 520 +/- 94 microg/ml; flavonoids and tannins are the main constituents; Na+ and K+ contents in 1.0 mg/ml of aqueous extract were 0.12 +/- 0.016 and 1.19 +/- 0.15 mM, respectively). The aqueous extract abolished the positive Bowditch staircase phenomenon and reduced the inotropic response to CaCl2 (0.17-8.22 mM), events that are dependent on the cellular Ca2+ inward current. The adrenergic, muscarinic or opioid membrane receptors do not seem to participate in the mechanism of action of the cardioactive substance(s). In spontaneously beating atria, the aqueous extract promoted a negative chronotropic effect that was antagonized by 0.1 microM isoproterenol bitartrate. With this agonist, the EC50 of the aqueous extract increased from 133 +/- 58 to 650 +/- 100 microg/ml. These data regarding the effect of A. carambola on guinea pig atrial contractility and automaticity indicate an L-type Ca2+ channel blockade.
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PMID:Negative inotropic and chronotropic effects on the guinea pig atrium of extracts obtained from Averrhoa carambola L. leaves. 1600 83

Drugs that inhibit the renin-angiotensin system (RAS), namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor antagonists (ARA) are gaining increasing popularity as initial medications for the management of hypertensive patients. In the year 2002, ACE-I were the most commonly prescribed drugs for the treatment of hypertension in USA. Although their antihypertensive efficacy as monotherapy is similar to other antihypertensive agents, they have the advantage of better tolerability, limited side effects and a favorable metabolic profile. When compared to other antihypertensive agents (diuretics, beta-adrenergic blockers and calcium antagonists) in large clinical trials, ACE-I and ARA provided no additional advantages regarding improvement in cardiovascular and total mortality. With the exception of the superiority of ARA in prevention of stroke, RAS inhibitors have no advantage over other agents in prevention of other cardiovascular morbid events, namely, heart failure (though ACE-I are superior to calcium antagonists), coronary heart disease and total cardiovascular events. However, there is the possibility that these agents have other benefits beyond blood pressure lowering. At equal degrees of blood pressure reduction, RAS inhibitors prevent or delay the development of diabetes mellitus and provide better end-organ protection, kidneys, blood vessels and the heart when compared with other antihypertensive agents. The combined use of ACE-I and ARA is particularly useful in organ protection. RAS inhibitors are specifically indicated in the treatment of hypertension in patients with impaired left ventricular systolic function, diabetes, proteinuria, impaired kidney function, myocardial infarction, multiple cardiovascular risk factors and possibly elderly patients. The main limitation of the ACE-I is cough and rarely angioedema. Elderly patients or those who are volume depleted or receiving large doses of diuretics or in heart failure are liable to develop hypotensive reaction and/or deterioration in kidney function.
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PMID:RAS inhibition in hypertension. 1639 19


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