Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bradykinin stimulates diverse functions in endothelial cells including the release of endothelium-derived relaxing factor (EDRF). Little is known, however, regarding the identity of the G protein(s) involved. Here we demonstrate that G proteins of the G alpha i and G alpha q family are coupled to the bradykinin receptor (BKR) in bovine aortic endothelial cells by using specific antisera directed against the COOH-terminal region of G alpha i2 (P4), G alpha i3 (EC), and G alpha q (QL). These antisera are specific since their effects are blocked by the decapeptides from which they were derived. The degree of receptor-G protein coupling was assessed by the formation of high affinity agonist binding sites (HABS) and GTP hydrolysis. In a concentration-dependent manner, the QL antisera reduced HABS and GTPase activity by 65 and 60%, respectively, and effectively abolished them in membranes from pertussis toxin-treated cells. The combination of P4 and EC antisera produced a loss of HABS (41%) and GTPase activity (40%) comparable to the effects of pertussis toxin. These findings indicate that G alpha i and G alpha q proteins mediate the cellular responses to bradykinin in bovine aortic endothelial cells and support the observation that bradykinin-stimulated EDRF release is relatively insensitive to pertussis toxin.
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PMID:The G proteins of the G alpha i and G alpha q family couple the bradykinin receptor to the release of endothelium-derived relaxing factor. 822 32

Short periods of ischemia render the myocardium more resistant to a subsequent prolonged coronary occlusion resulting in a reduction of infarct size. This cardioprotective mechanism has been called ischemic preconditioning. Acute myocardial ischemia results in a rapid decline of high energy phosphates. After short periods of ischemia the high energy phosphate levels are better preserved and the increase of lactate is slower during the prolonged subsequent ischemia in the preconditioned group compared to control. The duration of ischemia needed for induction of the protective effect is 2.5 min in dogs and 20 min in our swine model. In porcine myocardium the protection is lost about 1 h after induction and a renewal is not possible at that time, but is 24 h later. For rabbits or dogs, but not in pigs, a late protection 24 h after induction or preconditioning has been shown ("second window of protection"). Adenosine or adenosine A1 receptor agonists, muscarinic M2 receptor agonists, alpha 1-receptor agonists and bradykinin B2 receptor agonists as well as opening of the K+ATP-channel substitute for ischemia in the induction of protection. Activation of protein kinase C results in protection in rats and rabbits, but not in dogs or pigs. Inhibition of protein kinase C translocation or kinase activity results in a loss of the protection induced by preceding ischemia. After blockade of the K+ATP-channel the protection induced by adenosine A1 receptor activation is lost. Therefore opening of the K+ATP-channel is a prerequisite for induction of the protective effect. Inhibition of the inhibitory G-protein by pertussis toxin has been shown to result in a loss of protection, therefore the Gi-protein seems to be involved in the evolution of protection. In humans during coronary angioplasty anginal pain and lactate production during a second balloon occlusion is diminished without any change in the regional myocardial perfusion. This adaptation is inhibited by blockade of the K+ATP-channel or of the adenosine A1 receptor. Intermittent cross-clamping before a longer occlusion during open-heart surgery results in a better preservation of high energy phosphates compared to controls without preceding short ischemia. These observations support the hypothesis that ischemic preconditioning also occurs in humans. Angina pectoris preceding the myocardial infarction may have preconditioned the human heart against the subsequent myocardial infarction, but studies concerning the influence of angina pectoris on short-term outcome after thrombolysis are conflicting. In the future, ischemic preconditioning or preconditioning with drugs may prolong the duration of ischemia tolerated without necrosis and improve the prognosis of patients by reducing the infarct size.
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PMID:-Myocardial protection by preconditioning. Experimental and clinical significance-. 865 Sep 86

Bradykinin is a mediator of the protection of myocardium by angiotensin I-converting enzyme/kininase II inhibitors. We reported that the activation of B2 bradykinin receptors in neonatal rat cardiac myocytes in primary culture was followed by hydrolysis of phosphatidylinositol 4,5-bisphosphate and formation of inositol 1,4,5-trisphosphate (IP3). Here we examine the regulation of IP3 formation stimulated by bradykinin. Activation of myocytes with 1 mu/L bradykinin increased IP3 production from 117 +/- 8.3 to 1011 +/- 48.6 pmol/mg protein. Treatment of the cells with 10 mu/L indomethacin or 1 mu/L dexamethasone partially blocked this bradykinin-induced response. Moreover, either U73122, a phospholipase C inhibitor, or (p-amylcinnamoyl) anthranilic acid, a phospholipase A2 inhibitor, blunted the IP3 response to bradykinin. Because thromboxane A2 stimulates inositol bisphosphate metabolism in guinea pig atria, we also investigated the effect of the thromboxane A2 receptor antagonist BM 13177 (1 mu/L), which strongly attenuated the stimulated IP3 production. Since thromboxane A2 appears to partly mediate the IP3 response to bradykinin, we examined the effect of the stable thromboxane A2 mimetic U46619. Control cultures were stimulated more by U46619 than by bradykinin (1629 +/- 14.5 versus 1011 +/- 48.6 pmol IP3/mg protein). This property of U46619 was selectively antagonized by BM 13177. Inhibition of either phospholipase C or phospholipase A2 blunted the IP3 response to U46619. Short-term (30 minutes) activation of protein kinase C with phorbol 12-myristate 13-acetate (10 pmol/L to 1 mu/L) attenuated the IP3 accumulation in response to bradykinin; the effect of phorbol 12-myristate 13-acetate was reversed with 1 mu/L staurosporine, a protein kinase C inhibitor. Treatment with 1 microgram/mL cholera toxin or pertussis toxin for 4 hours amplified the IP3 response to 10 nmol/L bradykinin from 570 +/- 20.0 to 1150 +/- 51.3 and to 1016.7 +/- 21.9 pmol/mg protein. Bradykinin mobilized 9.4% of intracellular calcium stores in cardiomyocytes as assessed by chlortetracycline-based fluorometry, and this effect of bradykinin was blocked by BM 13177 or the B2 bradykinin receptor blocker Hoe 140 by more than 70%. In functional studies, bradykinin (1 mu/L) increased by 12% the twitch contractile force of neonatal rat ventricular strips paced at threshold intensity, but this was unaffected by BM 13177. In conclusion, in cardiomyocytes, bradykinin enhances IP3 production mostly via phospholipase A2 stimulation and thromboxane A2 formation. This prostanoid in turn stimulates its receptor and activates phospholipase C, which then splits phosphatidylinositol 4,5-bisphosphate into IP3 and diacylglycerol. The effect of bradykinin on phospholipase C, via thromboxane A2, is negatively regulated by protein kinase C activation.
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PMID:Thromboxane A2 mediates the stimulation of inositol 1,4,5-trisphosphate production and intracellular calcium mobilization by bradykinin in neonatal rat ventricular cardiomyocytes. 879 31

The bradykinin regulation of calcium channel currents in NG108-15 neuroblastoma x glioma hybrid cells was examined, in order to determine: (1) which type of bradykinin receptors mediates the inhibition of N-type calcium channels in these cells; and (2) whether bradykinin can modulate other types of calcium channels in these cells. Bradykinin inhibited both N- and L-type calcium channels in NG108-15 cells, with EC50S of 10 +/- 2 nM and 29 +/- 7 nM, respectively. The inhibition of both L- and N-type calcium channels by bradykinin (100 nM) could be completely inhibited by the bradykinin B2 receptor antagonist Hoe 140 (10 nM). Bradykinin appeared to inhibit that portion of the L-type calcium channel current that was also reversibly inhibited by omega-conotoxin GVIA. The bradykinin inhibition of the L-type calcium channel current was partly reduced by pretreatment of the cells with pertussis toxin, whereas the inhibition of the N-type current was pertussis toxin-insensitive. In some cultures it was observed that the bradykinin B1 receptor agonist desArg9bradykinin inhibited the L-type calcium channel current.
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PMID:Bradykinin inhibition of N- and L-type calcium channel currents in NG108-15 cells. 914 48

In a previous publication we provided evidence of a novel neuronal pathway for the control of GnRH secretion by bradykinin. The action of bradykinin appeared to be exerted through the bradykinin B2 receptor. In this study we demonstrated that the bradykinin B2 receptor is densely localized in the arcuate nucleus, median eminence, organum vasculosum of the lamina terminalis, and preoptic area, regions known to be critical for the control of GnRH secretion. To determine the mechanism of action of bradykinin in stimulating GnRH release, we used immortalized GnRH (GT1-7) cells in vitro. Bradykinin stimulation of GnRH secretion from GT1-7 cells appears to involve activation of the phospholipase C signaling pathway and mobilization of extracellular and intracellular calcium stores. Evidence to support this contention was derived from the observations that incubation of the phospholipase C inhibitor, U-73122 with bradykinin, blocked the ability of bradykinin to stimulate release from GT1-7 cells. This effect was specific, as a nitric oxide synthase inhibitor and a cyclooxygenase inhibitor were found to have no effect on bradykinin-induced GnRH secretion, suggesting that nitric oxide and PGs do not mediate bradykinin effects. Pertussis toxin also had no effect on bradykinin action. This suggests that the bradykinin B2 receptor may be coupled to a pertussis toxin-insensitive G protein in GT1-7 cells. With respect to calcium involvement in bradykinin action, fura-2 calcium indicator studies revealed that bradykinin can rapidly increase intracellular Ca2+ levels in GT1-7 cells. A role for intracellular Ca2+ in bradykinin action was further suggested by the finding that an intracellular calcium chelator, 1,2-bis(O-aminophenoxy)]ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester, significantly attenuated the effects of bradykinin on GnRH release. The elevation of intracellular calcium by bradykinin appears to be due to mobilization of calcium from the endoplasmic reticulum, as incubation of the Ca2+-adenosine triphosphatase inhibitor thapsigarin, which depletes endoplasmic reticulum Ca2+ stores, significantly attenuated bradykinin action on GnRH release. Extracellular calcium may also be involved in bradykinin action, as the L-type Ca2+ channel blockers verapamil and nifedipine had no effect on bradykinin-induced GnRH release, whereas the nonselective Ca2+ channel blocker, nickel chloride, attenuated bradykinin-induced GnRH release. Taken as a whole, these studies demonstrate that the bradykinin B2 receptor is densely localized in key hypothalamic nuclei responsible for regulation of GnRH release, and that the mechanism of bradykinin stimulation of GnRH secretion involves activation of the phospholipase C signaling pathway, with a critical role implicated for calcium in bradykinin action in GT1-7 cells.
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PMID:Bradykinin receptor localization and cell signaling pathways used by bradykinin in the regulation of gonadotropin-releasing hormone secretion. 1049 24

The relationship between cell proliferation, protein tyrosine phosphorylation, phosphotyrosine kinase activity and bradykinin receptor activation in rat mesangial cells was investigated. We demonstrated that bradykinin (BK), through the B2 receptor, induced a dose-dependent inhibition of mesangial cell proliferation stimulated by fetal calf serum. We next found that BK induced a dose-dependent inhibition of phospho-tyrosine kinase activity. Treatments with pertussis-toxin, inhibition of phospholipase C and protein kinase C inhibitors and chelation of free cytosolic calcium did not change the bradykinin-induced inhibition of phosphotyrosine kinase. Western blot analysis of phosphotyrosinated proteins demonstrated that BK reduced tyrosine phosphorylation of several proteins among which we identified the 125-focal adhesion kinase. Taken together, these data suggest for the first time that, in proliferating rat mesangial cells, B2 receptor stimulation is able to induce, via a pertussis insensitive pathway, the inhibition of tyrosine kinase activity and mesangial cell proliferation.
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PMID:Bradykinin-induced inhibition of cell proliferation and tyrosine kinase activity in rat mesangial cells. 1060 80

Angiotensin I-converting enzyme (ACE, kininase II) has 2 active domains (N and C) in a single peptide chain. Because we found its N-domain more stable than its C-domain, we investigated the effect of the amino-terminus of human ACE on the C-domain with a molecular construct expressed in Chinese hamster ovary cells (CHO) cells and transiently in HEK293 cells. This active N-deleted ACE contained only the first 141 amino acids of the human N-domain but not its active center and was linked to the active C-domain containing the transmembrane and cytosolic portions of ACE. The CHO cells were also transfected with human B(2) bradykinin receptor. ACE inhibitors (5 nmol/L or 1 micromol/L) augmented bradykinin (100 nmol/L) effects, elevated B(2) receptor numbers, and resensitized the receptor desensitized by agonist as measured by arachidonic acid release or [Ca(2+)](i) mobilization. Arachidonic acid release was mediated by pertussis toxin-sensitive G alpha(i), and [Ca(2+)](i) mobilization was mediated by pertussis-insensitive G alpha(q) protein receptor complex. The properties of the construct were compared with wild-type ACE and separate N- and C-domains. The N-deleted ACE differed from wild-type in activation by Cl(-) and [SO(4)](2-) ions, hydrolysis ratios of substrates (both short synthetic and endogenous peptides) and heat stability. Thus, the N-terminal peptide of ACE affected the characteristics of the C-domain active center. ACE inhibitors acting on N-deleted ACE, which had only a single C-domain active center anchored to plasma membrane, induced cross-talk between the enzyme and the B(2) receptor (eg, the inhibitors resensitized the receptor) independent of blocking bradykinin inactivation.
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PMID:Effects of the N-terminal sequence of ACE on the properties of its C-domain. 1090 22

We used a cultured murine cell model of the inner medullary collecting duct (mIMCD-3 cells) to examine the regulation of the ubiquitous sodium-proton exchanger, Na+/H+ exchanger isoform 1 (NHE-1), by a prototypical G protein-coupled receptor, the bradykinin B2 receptor. Bradykinin rapidly activates NHE-1 in a concentration-dependent manner as assessed by proton microphysiometry of quiescent cells and by 2'-7'-bis[2-carboxymethyl]-5(6)-carboxyfluorescein fluorescence measuring the accelerated rate of pH(i) recovery from an imposed acid load. The activation of NHE-1 is blocked by inhibitors of the bradykinin B2 receptor, phospholipase C, Ca2+/calmodulin (CaM), and Janus kinase 2 (Jak2), but not by pertussis toxin or by inhibitors of protein kinase C and phosphatidylinositol 3'-kinase. Immunoprecipitation studies showed that bradykinin stimulates the assembly of a signal transduction complex that includes CaM, Jak2, and NHE-1. CaM appears to be a direct substrate for phosphorylation by Jak2 as measured by an in vitro kinase assay. We propose that Jak2 is a new indirect regulator of NHE-1 activity, which modulates the activity of NHE-1 by increasing the tyrosine phosphorylation of CaM and most likely by increasing the binding of CaM to NHE-1.
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PMID:Bradykinin B2 receptors activate Na+/H+ exchange in mIMCD-3 cells via Janus kinase 2 and Ca2+/calmodulin. 1127 60

The effects of bradykinin on nicotine-induced responses were investigated in neurons dissociated from rat paratracheal ganglia using the nystatin-perforated patch-clamp recording technique. When bradykinin (10(-9) to 10(-8) M) was pretreated and then simultaneously applied with 10(-5) M nicotine, bradykinin potentiated the nicotine-induced currents. The potentiation was mimicked by [Hyp3]-bradykinin and inhibited by HOE-140, pertussis toxin, neomycin and U-73122, but not U-73433. These results suggest that bradykinin potentiates nicotinic currents via bradykinin B2 receptor, pertussis toxin-sensitive G-protein and phospholipase C. Since bradykinin inhibits the M-current via bradykinin B2 receptor and pertussis toxin-insensitive G-protein [Mochidome, T., Ishibashi, H., Takahama, K., 2001. Bradykinin activates airway parasympathetic ganglion neurons by inhibiting M-currents. Neuroscience 105, 785-791.], it seemed that bradykinin B2 receptor activated two distinct signal transduction pathways in the paratracheal ganglia neurons. This effect of bradykinin might cause enhanced synaptic transmission in paratracheal ganglia neurons and contribute to the aggravation of pathological conditions of the lower airway via enhanced acetylcholine release from the postganglionic nerve terminals.
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PMID:Potentiation of nicotinic currents by bradykinin in the paratracheal ganglia neurons of rats. 1644 93

HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A(2) (PLA(2))/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeutic effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca(2+)-mobilization and enhanced bradykinin-promoted Ca(2+)-mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPARgamma agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs.
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PMID:Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A. 1667 24


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