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)

The bradykinin B2 receptor (BDKRB2) has high affinity for the intact kinins, which mediate a wide spectrum of biological effects, including pain, inflammation, vasodilation, and smooth muscle contraction and relaxation. In the present study, we have cloned and sequenced the gene encoding human bradykinin B2 receptor from a human genomic library. The B2 receptor gene contains three exons separated by two introns. The first and second exons are noncoding, while the third exon contains the full-length coding region, which encodes a protein of 364 amino acids forming 7 transmembrane domains. The human B2 gene shares high sequence identity with rat and mouse B2 receptor genes and significant similarity with the gene encoding the angiotensin II type I receptor in the nucleotide sequence and exon-intron arrangement. In the 5' flanking region, a consensus TATA box and several putative transcription factor-binding sites have been identified. Genomic Southern blot analysis showed that the B2 receptor is encoded by a single-copy gene that was localized to chromosome 14q32 by in situ hybridization. In a Southern blot analysis following reverse transcription and polymerase chain reaction, the human B2 receptor was found to be expressed in most human tissues.
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PMID:Structure and chromosomal localization of the gene (BDKRB2) encoding human bradykinin B2 receptor. 783 85

Bradykinin is a nonapeptide that plays a central role in the production of pain and inflammation. A horizontal spinal cord slice preparation with attached dorsal root and dorsal root ganglion was used to study the effect of bradykinin on afferent fibers. Intracellular recordings were made from dorsal root ganglion and dorsal horn neurons. Bath application of bradykinin (1 microM) to the dorsal root ganglion compartment produced a depolarization (5 +/+ 0.8 mV) and firing of action potentials in eight out of eighteen dorsal root ganglion neurons tested. Simultaneous intracellular recordings from dorsal horn neurons revealed that the application of bradykinin to dorsal root ganglion, peripheral nerve trunk or dorsal root resulted in the synaptic activation of dorsal horn neurons. The depolarizing effect of bradykinin on the dorsal root ganglion neurons and its synaptic excitatory effect on dorsal horn neurons was abolished by pretreatment of the same segment of sensory neurons by a B2 bradykinin receptor antagonist (D-Arg0,Hyp3,beta-Thi5,8,D-Phe7)-bradykinin (5 microM). Bath application of tetrodotoxin (TTX; 0.2-1 microM) to the sensory neurons blocked electrically-evoked action potentials in large dorsal root ganglion neurons and, consequently, excitatory postsynaptic potentials in dorsal horn neurons evoked by electrical activation of low threshold afferent fibers. However, the stimulatory effects, both depolarization and firing of action potentials, of bradykinin were resistant to TTX. Replacement of sodium ions with TRIS completely abolished the stimulatory effect of bradykinin on the sensory neurons. Bradykinin potentiated the postsynaptic potentials induced by electrical stimulation of TTX-resistant afferent fibers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bradykinin excites tetrodotoxin-resistant primary afferent fibers. 788 21

1. Porphyromonas gingivalis is one of the bacteria likely to be related to pain in periodontitis. Several enzymes isolated from P. gingivalis have been reported to have kininogenase activity. Since kinin release could be held responsible for inflammatory symptoms and pain in periodontitis, we investigated whether the inflammatory and algesic effects of a sonic extract from P. gingivalis (PGSE) could be inhibited by the potent bradykinin B2 receptor antagonist, icatibant (Hoe 140). 2. In anaesthetized rats, the subplantar injection of PGSE (0.1 and 1.0 mg) caused a dose-dependent oedema of the hind paws. The net increase of the paw volume 60 min after the injection was 23 +/- 5% and 77 +/- 12%, respectively. The oedema was rich in plasma proteins as determined by the Evans blue method. Pretreatment with icatibant (300 nmol kg-1, s.c.) significantly reduced the effect of 1.0 mg of PGSE whereas the effects of 0.1 mg of PGSE remained unaffected. 3. The subplantar injection of 1.0 mg of PGSE in unanaesthetized rats caused nociceptive behavioural responses which started about 5 min after the injection and lasted for about 10-15 min. These responses were completely prevented by pretreatment with icatibant (300 nmol kg-1, s.c.). 4. The present results show that the plasma extravasation induced by non-algesic doses of a sonic extract from P. gingivalis are caused by mechanisms other than B2 kinin receptor activation whereas inflammatory effects of algesic doses are due to the action of kinins. The pain elicited by the extract is solely mediated by kinins and can be prevented by icatibant. The bradykinin antagonist could thus have a potential for a clinical use against pain associated with periodontal inflammation.
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PMID:Anti-inflammatory and analgesic activity of the bradykinin antagonist, icatibant (Hoe 140), against an extract from Porphyromonas gingivalis. 795 58

Kinins are vasoactive paracrine peptides which participate in a wide range of functions, including the regulation of local organ blood flow, systemic blood pressure, transepithelial water and electrolyte transport, cellular growth, capillary permeability and inflammatory response, and pain. The recent introduction of specific bradykinin receptor subtype antagonists has greatly advanced our understanding of the role of the kallikrein-kinin system (KKS) in various physiological and disease states. However, a major gap remains in our knowledge of the role of kinins in early development. In this review, evidence is presented that the developing nephron expresses both tissue kallikrein and kininogen, and that the genes encoding the components of the KKS are subject to considerable developmental regulation. The activity of the intrarenal kinin-generating system is lowest in the developing kidney and increases with age. Completion of nephrogenesis is characterized by a marked surge in intrarenal kallikrein synthesis and gene transcription. Maturation is associated with redistribution of intrarenal kallikrein and its messenger RNA from the inner to outer cortical nephrons following the centrifugal pattern of nephron development. Challenges for the future include delineation of the direct role of kinins in the maturation of renal functions and elucidation of the molecular mechanisms underlying the developmental expression of the KKS.
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PMID:Molecular aspects of kallikrein and kininogen in the maturing kidney. 825 40

Bradykinin may be generated in the heart during ischemia and is involved in nociception. We tested the hypothesis that bradykinin elicits a sympathoexcitatory reflex in rats by stimulating cardiac afferent nerve fibers. Rats were implanted with femoral catheters for measurement of blood pressure and heart rate, a bipolar electrode for measurement of renal sympathetic nerve activity, and a pericardial catheter for intrapericardial injection of substances. Rats were slightly anesthetized with hexobarbital so pain reactions were prevented. Graded doses of bradykinin (2.5, 12, 25 micrograms) were injected intravenously or intrapericardially into control rats, intrapericardially after vagotomy, intrapericardially after intrapericardial pretreatment with the bradykinin B2 receptor antagonist Hoe 140, and intrapericardially after cardiac autonomic blockade (intrapericardial pretreatment with 10% procaine). For comparison, the serotonin 5-HT3 agonist phenylbiguanide, a substance known to elicit sympathoinhibitory reflexes by cardiac vagal afferents, and adenosine, putatively inducing sympathoexcitatory responses via the heart, were applied intrapericardially. Bradykinin increased blood pressure when administered intrapericardially but decreased blood pressure when injected intravenously; both intrapericardial and intravenous bradykinin increased renal sympathetic nerve activity. Intrapericardial adenosine had no effect on circulatory control. Intrapericardial pretreatment with the B2 receptor antagonist Hoe 140 completely inhibited the increases of blood pressure and renal sympathetic nerve activity in response to intrapericardial bradykinin but did not affect the responses to intrapericardial phenylbiguanide. Bilateral cervical vagotomy abolished the decreases of blood pressure, heart rate, and renal sympathetic nerve activity after intrapericardial phenylbiguanide but did not influence the responses to intrapericardial bradykinin. Cardiac autonomic blockade with intrapericardial procaine abolished all responses to bradykinin and phenylbiguanide. We conclude that cardiac bradykinin elicits a sympathoexcitatory reflex by epicardial B2 receptors in rats. The afferent portion of the reflex is most likely contained within sympathetic cardiac afferent fibers. Bradykinin may contribute to increased sympathetic nerve activity in pathophysiological situations of coronary artery disease and cardiac ischemia.
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PMID:Epicardial bradykinin B2 receptors elicit a sympathoexcitatory reflex in rats. 884 87

The endogenous nonapeptide bradykinin is a powerful substance which activates nociceptors, resulting in the sensation of pain in man. We used a newly developed non-radioactive method to detect bradykinin binding sites in isolated dorsal root ganglion cells with gold-labelled bradykinin. In a subpopulation of cells, gold-labelled bradykinin was bound in different quantities. The proportion of somata with bradykinin binding markedly depended on the length of time in culture. After 0.75 days, bradykinin was bound to 43% of somata. This proportion increased to 85% after 1.75 days and then decreased to 27% after 5.75 days. Bradykinin was bound to cells of all sizes, ranging from 40 to 2000 microns2 with a maximum of 200-300 microns2. In some cells, binding was also seen along the processes. No correlation was found between the soma size and the density of bradykinin binding. Blocking the bradykinin binding at the B1 receptor with (Des-Arg10)-Lys-bradykinin and at the B2 receptor with D-Arg(Hyp3-Thi5.8-D-Phe7)-bradykinin, respectively, revealed that in 0.75-day-old cultures no or only a very small amount of B1 receptors are present. In 1.75-day-old cultures, the marked increase in the proportion of cells with positive bradykinin binding is due to a de novo expression of the B1 receptor subtype and an up-regulation of the B2 receptor subtype. The selective or combined addition of specific B1 and B2 receptor ligands revealed that both receptor subtypes are co-localized. These data show that cultured sensory neurons express not only B2, but during a short period of time in culture also B1 receptors. The data allow us to hypothesize that a transient increase in bradykinin receptor expression might be caused by cell injury due to disruption of the axon. The injury-induced up-regulation of the receptor in vivo could cause physiological reactions.
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PMID:Bradykinin receptors in cultured rat dorsal root ganglion cells: influence of length of time in culture. 893 54

Bradykinin binds to its receptor at target organs and exerts a wide spectrum of biological activities including vasodilation, smooth muscle contraction and relaxation, pain, and inflammation. To gain a better insight into the physiological function of this potent vasoactive peptide, we created transgenic mice that harbor the human bradykinin B2 receptor transgene under the control of the Rous sarcoma virus 3'-LTR promoter (RSV-cHBKR). Expression of HBKR in these transgenic mice was identified in the aorta, brain, heart, lung, liver, kidney, uterus, and prostate gland by reverse transcription-polymerase chain reaction Southern blot analysis. Two transgenic mouse lines expressing the human B2 receptor resulted in a significant reduction of blood pressure (84.2 +/- 0.6 mm Hg, n = 28; 76.9 +/- 0.8 mm Hg, n = 24; P < .001) compared with the control littermates (96.9 +/- 0.4 mm Hg, n = 52). Administration of Hoe 140, a bradykinin B2 receptor antagonist, restored the blood pressure of the transgenic mice to normal levels within 1 hour, and the effect diminished within 4 hours. The transgenic mice displayed enhanced blood pressure-lowering effect induced by a bolus intra-aortic injection of kinin and showed increased response in kinin-induced uterine smooth muscle contractility compared with control littermates. These studies show that overexpression of human bradykinin B2 receptor causes a sustained reduction of blood pressure in transgenic mice. They also suggest that the B2 receptor-mediated signal transduction pathway plays a role in blood pressure regulation.
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PMID:Hypotension in transgenic mice overexpressing human bradykinin B2 receptor. 903 47

1. The last decade has witnessed a phenomenal increase in our understanding of the pharmacology of bradykinin receptors, and has led to an appreciation of a key role for the peptide kinins as proinflammatory mediators. This short review summarises the major changes that have taken place in the expanding area of bradykinin receptor pharmacology, and highlights important advances that we hope to anticipate in the future. 2. Bradykinin receptors are cell surface, G-protein coupled receptors of the seven-transmembrane domained family. The existence of two subtypes of bradykinin receptor, B1 and B2, has been confirmed through the use of high affinity peptide and nonpeptide receptor antagonists, radioligand binding studies and, recently, receptor cloning and expression studies. 3. Differences in the affinities of B2 receptor antagonists, including those of the [D-Phe7]-bradykinin series, D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin (Hoe140, Icatibant) and the non-peptide, WIN64338, have led to proposals of the possible existence of further subtypes of bradykinin receptor (including a tracheal B3 receptor), and/or of species homologues of the B2 receptor. 4. Molecular cloning techniques have identified the gene encoding B1 receptors in the rabbit, human and mouse, and B2 receptors in the rat, human and mouse. B1 and B2 receptor show little (36%) overall sequence homology. Cloning studies reveal the potential for the existence of species homologues of receptors. 5. The use of bradykinin receptor antagonists in vivo has led to an appreciation of the involvement of bradykinin receptors in inflammation. Evidence suggests a role for B2 receptors in more classical acute inflammatory events, such as oedema and inflammatory pain, whereas B1 receptors appear to be involved in chronic inflammatory responses, including certain forms of persistent hyperalgesia. 6. The continuing advances in our knowledge of the characteristics of bradykinin receptors through the further development of selective receptor antagonists and molecular biology techniques will aid in the rational design of drugs effective in the therapeutic manipulation of inflammatory processes and in the control of inflammatory disease.
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PMID:Bradykinin receptors. 911 69

Kinins (bradykinin, kallidin) are produced at sites of injury and inflammation and serve a critical role in signaling tissue distress as well as organising tissue responsiveness to injury. The acute activation and prolonged sensitization of fine afferents, to produce pain and hyperalgesia, are important in the protective responses that occur to minimize further tissue injury. These effects occur via activation of B2 receptors present on sensory neurons, resulting in a change of membrane excitability and altered cellular neurochemistry. B2 receptor activation of a variety of tissues including postganglionic sympathetic fibres stimulates the production of several proinflammatory mediators, including prostanoids and cytokines, which interact with kinins and contribute to inflammation and hyperalgesia. Increased expression of B1 receptors plays a prominent role in inflammatory hyperalgesia, but further characterization of the cellular mechanism is required. A role for kinins and kinin receptors in central pathophysiologies (trauma, ischemia, infection) needs examination. The evidence for modulation of nociception and central pain generation is compelling, as central bradykinin administration causes hyperalgesia, whereas B2 antagonists are antinociceptive. The basis for these effects should be urgently investigated. Such data will add further support to the utilization of bradykinin receptor antagonists for the treatment of peripheral and central pain.
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PMID:Kinins and their receptors in hyperalgesia. 927 52

1. The nonpeptide bradykinin B2 receptor antagonist, FR173657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-(2, 4-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl] phenyl]-N-methylaminocarbonylmethyl] acrylamide), was tested in models involving bradykinin-induced activation of primary afferent neurones in vitro and in vivo. 2. Bradykinin-induced contractions of the rabbit isolated iris sphincter muscle mediated by tachykinin release from trigeminal afferent neurones were inhibited in a non-competitive manner by FR173657. A pKB value of 7.9 was calculated. Effects of substance P were unaffected by FR173657. 3. Nociceptive behavioural responses following intraplantar injection of bradykinin in unanaesthetized rats were reduced by 0.3 micromol kg(-1) FR173657 s.c. (P < 0.05), and completely abolished by 3 micromol kg(-1) (P < 0.05). Peroral administration of 5 micromol kg(-1) FR173657 abolished the bradykinin effects (P < 0.05); lower doses had no significant effect. 4. Shortening by intraplantar injection of bradykinin of the paw withdrawal latency in response to radiant heat was abolished by 3 micromol kg(-1) FR173657 s.c. (P < 0.05), while 300 nmol kg(-1) had an intermediate effect. Hyperalgesia induced by prostaglandin E2 remained unaffected by FR173657. 5. Blood pressure reflexes following i.p. instillation of bradykinin in anaesthetized rats were inhibited by FR173657 s.c. with an ID50 of 1.1 micromol kg(-1), while the peptidic B2 antagonist icatibant (Hoe-140; D-Arg0-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) caused inhibition at significantly lower doses (ID50 8.5 nmol kg(-1) P < 0.001). Responses to hydrochloric acid i.p. remained unaffected by FR173657. 6. FR173657 or similar nonpeptide compounds may be useful for the development of drugs for diseases involving pain induced by the release of endogenous kinins, i.e. especially in acute inflammatory conditions.
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PMID:The nonpeptide B2 receptor antagonist FR173657: inhibition of effects of bradykinin related to its role in nociception. 972 Aug 8


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