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 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

Proposed mechanisms by which alpha 2-adrenergic receptors (alpha 2AR) regulate intracellular calcium ([Ca2+]i) include stimulation and inhibition of cell surface calcium channels, stimulation of calcium release via receptor coupling to Gq with subsequent activation of phospholipase C and release of IP3, or stimulation of calcium release via coupling to Gi in an IP3-independent manner. These potential mechanisms were explored in cells that expressed alpha(2A)AR endogenously (HEL cells), permanently transfected CHO cells, and transiently transfected COS-7 cells. Each cell type displayed agonist (UK14304)-dependent increases in [Ca2+]i that were blocked by yohimbine, ablated by pertussis toxin, and largely unaffected by chelation of extracellular calcium. Furthermore, calcium release was associated with IP3 accumulation and was blocked by an inhibitor of phospholipase C (PLC). When expressed in CHO cells, a mutated alpha(2A)AR which has the amino and carboxyl termini of the third intracellular loop substituted with beta 2AR sequence poorly coupled to Gi in adenylyl cyclase assays, and likewise displayed virtually no coupling to increased [Ca2+]i. These results all point toward a Gi- versus a Gq-mediated coupling pathway triggering release of intracellular calcium stores. The possibility that G(beta gamma) subunits released from alpha(2A)AR-Gi coupling is the mechanism of PLC activation was explored in COS-7 cells by coexpressing alpha(2A)AR with the G(beta gamma) inhibitors transducin or a carboxy-terminal portion of the beta AR kinase. Both beta gamma inhibitors markedly inhibited alpha(2A)AR modulation of [Ca2+]i while not affecting thromboxane A2 receptor mediated stimulation of [Ca2+]i via Gq coupling. Thus, alpha(2A)AR couple to calcium release via Gi-associated G(beta gamma) subunits. This coupling is present in multiple cell types and should be considered a major signal transduction pathway of this receptor.
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PMID:Alpha 2A-adrenergic receptor stimulated calcium release is transduced by Gi-associated G(beta gamma)-mediated activation of phospholipase C. 917 58

1. In vitro studies were performed to examine the mechanisms underlying substance P-induced enhancement of constriction rate in guinea-pig mesenteric lymphatic vessels. 2. Substance P caused an endothelium-dependent increase in lymphatic constriction frequency which was first significant at a concentration of 1 nM (115 +/- 3% of control, n = 11) with 1 microM, the highest concentration tested, increasing the rate to 153 +/- 4% of control (n = 9). 3. Repetitive 5 min applications of substance P (1 microM) caused tachyphylaxis with tissue responsiveness tending to decrease (by an average of 23%) and significantly decreasing (by 72%) for application at intervals of 30 and 10 min, respectively. 4. The competitive antagonist of tachykinin receptors, spantide (5 microM) and the specific NK1 receptor antagonist, WIN51708 (10 microM) both prevented the enhancement of constriction rate induced by 1 microM substance P. 5. Endothelial cells loaded with the Ca2+ sensing fluophore, fluo 3/AM did not display a detectable change in [Ca2+]i upon application of 1 microM substance P. 6. Inhibition of nitric oxide synthase by NG nitro-L-arginine (L-NOARG; 100 microM) had no significant effect on the response induced by 1 microM substance P. 7. The enhancement of constriction rate induced by 1 microM substance P was prevented by the cyclooxygenase inhibitor, indomethacin (3 microM), the thromboxane A2 synthase inhibitor, imidazole (50 microM), and the thromboxane A2 receptor antagonist, SQ29548 (0.3 microM). 8. The stable analogue of thromboxane A2, U46619 (0.1 microM) significantly increased the constriction rate of lymphangions with or without endothelium, an effect which was prevented by SQ29548 (0.3 microM). 9. Treatment with pertussis toxin (PTx; 100 ng ml-1) completely abolished the response to 1 microM substance P without inhibiting either the perfusion-induced constriction or the U46619-induced enhancement of constriction rate. 10. Application of the phospholipase A2 inhibitor, antiflammin-1 (1 nM) prevented the enhancement of lymphatic pumping induced by substance P (1 microM), without inhibiting the response to either U46619 (0.1 microM) or acetylcholine (10 microM). 11. The data support the hypothesis that the substance P-induced increase in pumping rate is mediated via the endothelium through NK1 receptors coupled by a PTx sensitive G-protein to phospholipase A2 and resulting in generation of the arachidonic acid metabolite, thromboxane A2 this serving as the diffusible activator.
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PMID:Evidence that the substance P-induced enhancement of pacemaking in lymphatics of the guinea-pig mesentery occurs through endothelial release of thromboxane A2. 928 91

F(2)-Isoprostanes are generated from a cyclooxygenase-independent oxidative modification of arachidonic acid. They are present in atherosclerotic plaques and are platelet activators as well as potent vasoconstrictors. Polymorphonuclear neutrophils are major players in ischemia/reperfusion injury and in restenosis after PTCA. The effects of 8-isoprostaglandin (PG) F(2alpha) on very rapid beta(2)-integrin-dependent adhesion was evaluated in human neutrophils in vitro by use of purified integrin as ligand. 8-Iso-PGF(2alpha) (1 nmol/L to 20 micromol/L) triggers a dose-dependent, very rapid neutrophil adhesion to human fibrinogen but not to the endothelial ligand intercellular adhesion molecule-1. Pretreatment with anti-ss(2)-integrin subtypes showed activation of CD11b/CD18 and CD11c/CD18. Adhesion triggering was completely prevented by pertussis toxin. SQ29,548, a specific antagonist of thromboxane A2 receptor, also dose-dependently prevented 8-iso-PGF(2alpha)-triggered neutrophil adhesion. 8-Iso-PGF(2alpha) did not trigger adhesion in human monocytes and lymphocytes and did not induce neutrophil chemotaxis or activation of the oxygen free-radical-forming enzyme NADPH-oxidase. These data highlight the role of 8-iso-PGF(2alpha) as a specific activator of rapid neutrophil adhesion and suggest its involvement in the pathogenesis of ischemia/reperfusion injury and in restenosis after PTCA. The effect is transduced via activation of the receptor for thromboxane A2.
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PMID:8-Iso-PGF2 alpha induces beta 2-integrin-mediated rapid adhesion of human polymorphonuclear neutrophils: a link between oxidative stress and ischemia/reperfusion injury. 1114 33

In the present experiment, we examined the effect of 8-iso-prostaglandin E(2) and 8-iso-prostaglandin F(2 alpha) on the release of noradrenaline from the isolated rat stomach. The postganglionic sympathetic nerves were electrically stimulated twice at 1 Hz for 1 min and test reagents were added during the second stimulation. 8-Iso-prostaglandin E(2) (10(-8)-10(-6) M) and 8-iso-prostaglandin F(2 alpha) (10(-7)-10(-5) M) dose-dependently reduced the evoked noradrenaline release, and these inhibitory potencies were as follows: 8-iso-prostaglandin E(2)>8-iso-prostaglandin F(2 alpha). The inhibitory effect of 8-iso-prostaglandin F(2 alpha), but not 8-iso-prostaglandin E(2), was abolished by 10(-6) M SQ-29548 ([1S-[1 alpha,2 alpha(Z),3 alpha,4 alpha]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino] methyl]-7-oxabicyclo[2,2,1]hept-2-yl]-5-heptenoic acid) (a prostanoid TP receptor antagonist). On the other hand, the inhibitory effect of 8-iso-prostaglandin E(2) was abolished by 10(-5) M AH-6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) (a prostanoid EP receptor antagonist), which also attenuated the inhibitory effects of ONO-AE-248 (16S-9-deoxy-9 beta-chloro-15-deoxy-16-hydroxy-17,17-trimethylene 19, 20-didehydro prostaglandin F(2)) (a selective EP(3) receptor agonist) on the evoked release of noradrenaline. The inhibitory effect of 8-iso-prostaglandin F(2 alpha), but not 8-iso-prostaglandin E(2), was abolished by pertussis toxin. These results suggest that 8-iso-prostaglandin F(2 alpha) inhibits noradrenaline release through TP receptors, whereas 8-iso-prostaglandin E(2) seems to inhibit noradrenaline release through EP(3) receptors, located on the gastric sympathetic nerve terminals in rats.
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PMID:Effects of 8-iso-prostaglandin E2 and 8-iso-prostaglandin F2 alpha on the release of noradrenaline from the isolated rat stomach. 1278 33

Thromboxane A2 receptor (TP) consists of two alternatively spliced isoforms, TPalpha and TPbeta, which differ in their cytoplasmic tails. In the present study, we examined the difference in signal transduction of TPalpha and TPbeta, using stably expressing cells of TPalpha and TPbeta. The cells expressing TPalpha (TPalpha-SC2) and TPbeta (TPbeta-SC15) were selected based on the similar binding sites of [3H]-SQ29548, a TP antagonist. U46619, a TP agonist, elicited phosphoinositide hydrolysis in TPalpha-SC2 and TPbeta-SC15 cells with a similar concentration-dependency. U46619 also caused the phosphorylation of extracellular signal-regulated kinase (ERK1/2) in both TPalpha-SC2 and TPbeta-SC15 cells. While the peak of the phosphorylation of ERK1/2 was observed 5 min after addition of U46619 in TPalpha-SC2 cells, the long lasting phosphorylation up to 60 min was in TPbeta-SC15 cells. U46619-induced phosphorylation of ERK1/2 at 5 min was inhibited by pertussis toxin in both cells, suggesting that G(i) is involved in the phosphorylation mediated via both TP isoforms. Interfering G(12/13) activity by overexpression of p115-RGS reduced U46619-induced ERK1/2 phosphorylation in TPbeta-SC15 cells, but not in TPalpha-SC2 cells. H89, an inhibitor of protein kinase A (PKA), reduced U46619-induced ERK1/2 phosphorylation in TPalpha-SC2 cells, but not in TPbeta-SC15 cells. These results indicate that G(i) may be involved in TP-mediated ERK1/2 phosphorylation in both isoforms. In addition, H89-sensitive kinase and G(12/13) may be involved in TP-mediated ERK1/2 phosphorylation in TPalpha and TPbeta, respectively.
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PMID:Different pathways for activation of extracellular signal-regulated kinase through thromboxane A2 receptor isoforms. 1659 6

This study was conducted to elucidate the molecular mechanisms of thromboxane A2 receptor (TP)-induced insulin resistance in endothelial cells. Exposure of human umbilical vein endothelial cells (HUVECs) or mouse aortic endothelial cells to either IBOP or U46619, two structurally related thromboxane A(2) mimetics, significantly reduced insulin-stimulated phosphorylation of endothelial nitric-oxide synthase (eNOS) at Ser(1177) and Akt at Ser(473). These effects were abolished by pharmacological or genetic inhibitors of TP. TP-induced suppression of both eNOS and Akt phosphorylation was accompanied by up-regulation of PTEN (phosphatase and tension homolog deleted on chromosome 10), Ser(380)/Thr(382/383) PTEN phosphorylation, and PTEN lipid phosphatase activity. PTEN-specific small interference RNA restored insulin signaling in the face of TP activation. The small GTPase, Rho, was also activated by TP stimulation, and pretreatment of HUVECs with Y27632, a Rho-associated kinase inhibitor, rescued TP-impaired insulin signaling. Consistent with this result, pertussis toxin abrogated IBOP-induced dephosphorylation of both Akt and eNOS, implicating the G(i) family of G proteins in the suppressive effects of TP. In mice, high fat diet-induced diabetes was associated with aortic PTEN up-regulation, PTEN-Ser(380)/Thr(382/383) phosphorylation, and dephosphorylation of both Akt (at Ser(473)) and eNOS (at Ser(1177)). Importantly, administration of TP antagonist blocked these changes. We conclude that TP stimulation impairs insulin signaling in vascular endothelial cells by selectively activating the Rho/Rho-associated kinase/LKB1/PTEN pathway.
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PMID:Thromboxane A2 receptor activates a Rho-associated kinase/LKB1/PTEN pathway to attenuate endothelium insulin signaling. 3151 59