Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bradykinin antagonists effective in a great variety of kinin-responsive tissues have been developed and used to study the roles of kinins in various physiological and pathological phenomena. Structural changes required to yield antagonists and to confer high potency, tissue selectivity, and resistance to enzymatic degradation have been explored in several hundred analogs. Certain of these offer promise for the development of drugs effective against pain, inflammation, and asthma.
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PMID:Kinin antagonists: design and activities. 169 64

A cDNA encoding a functional bradykinin receptor was isolated from a rat uterus library by a clonal selection strategy using Xenopus laevis oocytes to assay for expression of bradykinin responses. The predicted protein is homologous to the seven transmembrane G protein-coupled superfamily of receptors. Bradykinin and its analogs stimulate a Cl- current oocytes expressing the receptor with the rank order of potency: bradykinin approximately Lys-bradykinin greater than [Tyr8]-bradykinin much greater than [Phe6]bradykinin. This is the rank order of potency observed for these compounds in competitive binding assays on soluble receptor from rat uterus. Des-Arg9-bradykinin (10 microM) elicits no response when applied to oocytes expressing the receptor; thus, the cDNA encodes a B2 type bradykinin receptor. [Thi5,8,DPhe7]bradykinin, where Thi is beta-(2-thienyl)-alanine, is a very weak partial agonist and inhibits the bradykinin-mediated ion flux, suggesting the cDNA encodes a smooth muscle, rather than a neuronal, B2 receptor subtype. Receptor message has a distribution consistent with previous reports of bradykinin function and/or binding in several tissues and is found in rat uterus, vas deferens, kidney, lung, heart, ileum, testis, and brain. Receptor subtypes are a possibility because several tissues contain two or three message species (4.0, 5.7, and 6.5 kilobases). Southern blot high-stringency analysis demonstrated that the rat, guinea pig, and human genomes contain a single gene. As bradykinin is a key mediator of pain, knowledge of the primary structure of this receptor will allow a molecular understanding of the receptor and aid the design of antagonists for pain relief.
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PMID:Expression cloning of a rat B2 bradykinin receptor. 171 75

Pain and hyperalgesia, the perceptual campanions of tissue injury and inflammation, are thought to be in part attributable to the sensitization of primary afferent nociceptors by endogenously released chemicals, such as bradykinin. Bradykinin (0.1 to 10 nmol in 10 microliters) evoked a dose-dependent pain, hyperalgesia to heat stimuli, and wheal and flare when injected in a double-blind manner into the volar forearm intradermally. Though hyperalgesia to mechanical stimuli is a conspicuous feature of inflammatory pain, none was measurable for any of the bradykinin doses in response to graded nylon monofilament probes. A second injection of bradykinin (5- or 30-minute intervals) at the same site produced markedly less pain and hyperalgesia to heat stimuli, indicating that the algesic and hyperalgesic effects of bradykinin undergo tachyphylaxis. These findings suggest that bradykinin alone cannot account for all aspects of the hyperalgesia that occurs after inflammation.
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PMID:Pain and hyperalgesia after intradermal injection of bradykinin in humans. 175 17

Recent clinical observations suggest that adenosine may produce cardiac pain; even though the mechanisms involved still need defining, one of the most convincing hypotheses seems to be a direct adenosine stimulation of the sympathetic nerve endings present in the myocardium. In 10 decerebrate and artificially ventilated cats, single sympathetic afferent fibres innervating the left ventricle were isolated from the third white thoracic ramus communicans of the left sympathetic chain. After locations of the fibre receptor field on the cardiac surface, we evaluated the effects of the local epicardial application of adenosine (0.1, 1 and 10 mg/ml) on the nervous discharge activity. These results were compared with those obtained by application of bradykinin, a potent natural algogenic substance which activates sympathetic afferents, and by a mechanical stimulus such as a slight increase of systolic arterial pressure (46 +/- 6% from 113 +/- 18 mmHg) induced by partial occlusion of the thoracic aorta. In particular, adenosine (1 mg/ml) elicited a significant increase in impulse activity (from 0.11 +/- 0.02 to 0.36 +/- 0.06 imp/0.1 s) with a latency of 16 +/- 2 s. Bradykinin application (20 micrograms/ml), in the same way, produced a significant increase in impulse activity (from 0.11 +/- 0.01 to 0.86 +/- 0.16 imp/0.1 s) with a latency of 8 +/- 1 s. Neither situation showed significant hemodynamic changes. An increased neural discharge (from 0.11 +/- 0.02 to 0.26 +/- 0.04 imp/0.1 s) was also observed during aortic occlusion. After purinergic receptor blockade by aminophylline (5 mg/kg, iv), the response to adenosine was no longer observed, while responses to bradykinin and aortic occlusion were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The excitatory effect of adenosine on the discharge activity of the afferent cardiac sympathetic fibers]. 181 64

Bradykinin (BK) a nonapeptide generated in plasma during tissue injury, is involved in many physiological and pathological states. Kinin actions are mediated by specific membrane receptors and involve a complex signal transducer and also second messenger mechanisms. Due to its inequivocal relevance, an intensive effort has been focused in recent years to develop selective and competitive BK antagonists. Thus, the development of a new series of peptide BK antagonists has made an important contribution to the understanding of the pharmacological, physiological and pathophysiological role of BK, and this is certain to provide a firm basis for developing new drugs to relieve pain and inflammation. However, BK antagonists derived from peptide origin reported to date have limited clinical use due to their poor oral absorbtion and short duration of effect. Thus, considerable effort has also been made in developing stable nonpeptide BK antagonists. Up to now, most nonpeptide compounds reported to exhibit BK antagonistic activity have been derived from plants, including many flavonoids, terpenes, and also synthetic substances with various molecular structures. Amongst them, the pregnane glycoside compounds isolated from the plant Mandevilla velutina are the most promising. These compounds are effective in antagonizing BK responses in a variety of preparations, and they also exhibit potent and long-lasting analgesic and anti-inflammatory activities. The exact mechanism underlying their action however, is not yet completely understood.
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PMID:Natural bradykinin antagonists. 184 1

Pain was induced in 19 healthy individuals by double-blind injections into the forearm skin of 0.05 ml of physiological saline with or without active substances added. Bradykinin (0.5 nmol), 5-hydroxytryptamine (0.5 nmol) and a mixture of the two substances in half dosage (0.25 nmol + 0.25 nmol) caused significantly more pain than saline (p less than 0.05). The three test solutions also induced wheal and flare responses significantly more pronounced than saline. Bradykinin induced significantly more pain and more wheal than 5-hydroxytryptamine (p less than 0.05) but a significantly smaller flare (p less than 0.01). A dissociation between induced pain and flare was thus demonstrated.
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PMID:Pain, wheal and flare in human forearm skin induced by bradykinin and 5-hydroxytryptamine. 208 38

Bradykinin and its active metabolites are produced at the sites of their actions by kallikreins. They potently elicit a variety of biological effects: hypotension, bronchoconstriction, gut and uterine contraction, epithelial secretion in airway, gut, and exocrine glands, vascular permeability, pain, connective tissue proliferation, and eicosanoid formation. These effects are mediated by at least two broad classes of receptors. The most common is the B2 subtype. The Stewart and Vavrek peptides characterized by a DPhe7 substitution have provided powerful tools for study of bradykinin's actions by competitively and specifically blocking bradykinin B2 receptors. The significance of kinins in certain human diseases is being explored using these new tools and potential therapeutic agents. At present, human clinical trials are underway to test the usefulness of bradykinin receptor antagonists in the symptoms of the common cold and in the pain associated with severe burns. Trials for use in asthma will be initiated in 1990.
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PMID:Bradykinin receptor antagonists. 215 7

Bradykinin is the prime initiator of pain and the key initial activator of the inflammatory response at the site of tissue injury. The subsequent transfer of nociceptive information (pain sensation) into the central nervous system is then mediated via afferent type C dorsal root ganglion neurons. A recently developed hybrid cell line, F-11, shows many qualities characteristic of these pain-sensitive cells. In these neuronal hybrids, we have found that bradykinin induces sequential elevation in the concentrations of several second messengers involved in neuronal activation, including inositol trisphosphate (6.5-fold), intracellular calcium (2.7-fold), and cyclic GMP (20.5-fold). Importantly, the production of these second messengers is potently inhibited by several novel bradykinin antagonists that possess no intrinsic agonist activity. The same relative rank order of potency of inhibition of bradykinin-induced second messenger production was achieved in the inositol trisphosphate, calcium, and cyclic GMP assay systems, suggesting strongly that all three messenger systems are being activated by the same bradykinin receptor. The most potent antagonist was D-Arg0-Hyp3-Thi5,8-D-Phe7-bradykinin, which inhibited in a competitive manner, with pA2 values, upon Schild plot analysis, in the nanomolar range. These potent bradykinin antagonists may be useful in the characterization of bradykinin receptors and in the clinical management of pain and inflammation.
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PMID:Bradykinin analogs antagonize bradykinin-induced second messenger production in a sensory neuron cell line. 253 66

Bradykinin and its active metabolites, produced by kallikreins at their sites of action, potently elicit a variety of biological effects: hypotension, bronchoconstriction, gut and uterine contraction, epithelial secretion in airway, gut, and exocrine glands, vascular permeability, pain, connective tissue proliferation, cytokine release, and eicosanoid formation. These effects are mediated by at least two broad classes of receptors. The most common is the B2 subtype. The availability of competitive antagonists of B2 receptors has provided powerful tools for the study of bradykinin's actions. The significance of kinins in certain human diseases is being explored by using these agents as potential therapeutic agents. Human clinical trials are under way to test the usefulness of bradykinin receptor antagonists to treat symptoms of the common cold and the pain associated with severe burns. Trials are also being comtemplated for use in treatment of asthma.
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PMID:Antagonists of B2 bradykinin receptors. 254 96

Bradykinin (BK) have been involved in a lot of pharmacological and biological effects including natriuresis, vasodilatation, inflammation and pain mediation. All these potent effects of BK are presumably mediated via one or more specific receptors which have been classified in two types named B1 and B2 receptors. In the kidney, specific binding have been reported successively in cortical epithelial membranes, in renomedullary interstitial cells and in cortical collecting tubules. Furthermore, since a large number of vasoactive compounds have been shown to regulate renal glomerular hemodynamics, we examined the binding of BK in rat glomerular membranes and the effect of variable salt diet on the density (Bmax) and the dissociation constant (KD) of this binding. Incubation of a radiolabeled bradykinin analog, [125I]-Tyr8-BK with a crude membrane preparation obtained from isolated rat glomeruli revealed a time dependent binding. The binding was saturable, reversible and was a linear function of protein membrane concentration. The radiolabeled Tyr8-BK bound to a single class of binding sites with an equilibrium dissociation constant (KD) of 2.75 +/- 0.7 nM and a density (Bmax) of 32.1 +/- 5.2 fmol/mg protein. [125I]-Tyr8-BK binding was reversed by bradykinin (Ki = 0.4 10(-9) M) and by other kinin analogs. However, Des-Arg9-BK had no effect on binding of the radiolabelled BK. These results are consistent with the presence of a B2-kinin like receptor in rat glomeruli. Low salt diet (during one month) and water deprivation (during 4 days) induced a decrease in the density of glomerular BK like receptors respectively (Bmax = 12.45 +/- 1.3 and 13.25 +/- 1.17 fmol/mg protein).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Evidence for a glomerular receptor for bradykinin in rats. Effect of sodium intake on density and affinity of the receptor]. 255 36


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