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: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the regulation mechanism of adrenomedullin (AM) production in blood vessels, we examined the effects of 30 substances on AM production in cultured rat vascular smooth muscle cells (VSMCs). Forskolin and 8-bromo-cAMP suppressed production and gene transcription of AM. Since VSMC expresses AM receptors coupled with adenylate cyclase, AM production may be regulated by intracellular cAMP concentration. Thrombin, vasoactive intestinal polypeptide and interferon-gamma also inhibited AM production, while angiotensin II, endothelin-1, bradykinin, substance P, adrenaline, phorbol ester and fetal calf serum stimulated AM production in VSMC. These results suggest that AM production is regulated by a variety of substances, indicating complex systems regulating AM production.
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PMID:Effects of vasoactive substances and cAMP related compounds on adrenomedullin production in cultured vascular smooth muscle cells. 764 78

1. The release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) from the dorsal horn of the rat spinal cord in vitro in response to dorsal root stimulation was measured by radioimmunoassay. 2. Stimulation of the dorsal roots (3 or 4 roots on each side) at 10 Hz for 5 min evoked a mean release (R1) of 134.3 +/- 17.5 (n = 10) fmol CGRP-LI; the release (R2) evoked by a second stimulation period 30 min later under control conditions was 77 +/- 10% (n = 10) of R1. Test compounds were applied to the preparation following release R1, and their effect calculated from the value of R2/R1. 3. Bradykinin (0.01-10 microM) had no significant effect on the basal release of CGRP-LI, but at 0.1-10 microM it increased 2-3 fold the release evoked by dorsal root stimulation. 4. This effect of bradykinin was prevented by indomethacin (10 microM), or by the B2-receptor antagonist, Hoe140 (1-10 microM). In the presence of Hoe140, bradykinin significantly reduced R2/R1; the explanation for this is not clear. 5. The B1-receptor agonist, Des-Arg9-bradykinin (10 microM), did not affect CGRP-LI release nor was the effect of bradykinin blocked by the B1-receptor antagonist, Des-Arg9-Leu8-bradykinin (10 microM). 6. Various prostaglandins were found to mimic the effect of bradykinin on CGRP-LI release. Their approximate order of potency was prostaglandin D2 (PGD2) = PGE1 > PGF2 alpha = PGE2; PGI2 was ineffective at 10 microM.7. Forskolin (30 muM) and 3-isobutyl l-methylxanthine (IBMX; 10 fM) also increased the evoked release of CGRP-LI.8. It is concluded that bradykinin acts on B2-receptors in the spinal cord, causing the formation ofprostanoids, which in turn cause an enhancement of neuropeptide release from primary afferent nerve terminals in the dorsal horn. This effect may be secondary to activation of adenylate cyclase. Because B2-receptors are mainly associated with primary afferent nerve terminals, it is likely that prostanoid production is also a function of these structures. Whether this action of bradykinin has any physiological function in nociceptive transmission remains unclear..
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PMID:Effect of bradykinin and prostaglandins on the release of calcitonin gene-related peptide-like immunoreactivity from the rat spinal cord in vitro. 767 28

We tested the hypothesis that prostacyclin and its stable analogue iloprost act as agonists of ATP-sensitive potassium channels (KATP) to induce vasodilation of the coronary circulation. The selective blocker of KATP, glibenclamide, was used as a probe for vasodilation mediated by KATP in saline-perfused rabbit hearts (constant flow, Langendorff preparation). Glibenclamide (10-300 nM) significantly increased coronary perfusion pressure and inhibited vasodilation induced by iloprost (1-30 nM), prostacyclin (10 nM), adenosine (0.3 microM), and cromakalim (0.1 microM), a known agonist of KATP. This potassium channel antagonist also inhibited vasodilation of rabbit hearts in response to 10 nM bradykinin in the presence of an inhibitor of nitric oxide synthase (30 microM NG-nitro-L-arginine). Because bradykinin-induced vasodilation is mediated by prostacyclin released from endothelial cells when nitric oxide synthesis is inhibited, these data indicate that glibenclamide is also effective against endogenous prostacyclin. The inhibitory effects of glibenclamide were selective: vasodilation induced by sodium nitroprusside (1-10 microM) or acetylcholine (1 microM) were not inhibited by this potassium channel antagonist. In addition, basal and bradykinin-stimulated release of 6-ketoprostaglandin F1 alpha was not affected by this antagonist of KATP. Glibenclamide also did not inhibit the activation of adenylate cyclase, as indicated by its lack of effect on adenosine 3',5'-cyclic monophosphate accumulation induced by iloprost (10 nM-1 microM) in bovine coronary arterial segments, a tissue in which iloprost-induced vascular smooth muscle relaxation is inhibited by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostacyclin-induced vasodilation in rabbit heart is mediated by ATP-sensitive potassium channels. 767 57

Bradykinin receptors have been identified in human gingival fibroblasts; the primary signal transduction pathways and their dependence on calcium have been characterized. Binding data revealed a calcium-independent binding of bradykinin to the cell membrane with a receptor density of 25,000 receptors per cell and a Kd of 1.6 nM. The bradykinin receptor-mediated activation of phospholipase C (PLC) resulted in an extensive and rapid stimulation of phosphoinositide metabolism. Using radioreceptor assay techniques, in the absence of LiCl, the inositol 1,4,5-trisphosphate (Ins 1,4,5P3) generation was found to be transient, with maximal levels attained within 15 s. An EC50 of 12 nM was observed for the accumulation of total inositol polyphosphates. The activation of phospholipase A2 (PLA2), and the subsequent release of arachidonic acid and the primary metabolite prostaglandin E2, also was found to be time- and concentration-dependent. Stimulation of tyrosine kinase activity by bradykinin was concentration-dependent and resulted in the phosphorylation of three substrates of unknown identity. Bradykinin stimulation did not activate adenylate cyclase as there occurred no increase in the generation of cyclic AMP. The mobilization of intracellular calcium stores followed closely the Ins 1,4,5 P3 kinetics and had an EC50 of 11 nM. Chelation of extracellular calcium reduced significantly the duration of the calcium response, while only minimally lowering the rapid, maximal increase in intracellular free calcium concentration ([Ca2+]i). A sustained elevation of [Ca2+]i was found to be essential in PLC and PLA2 signaling, as well as in tyrosine kinase activation, suggesting a major role for membrane calcium channels in bradykinin stimulation of cellular responses in these cells. Bradykinin was found to inhibit dramatically epidermal growth factor-induced DNA synthesis in confluent cells, although to a much lesser degree in subconfluent cells. This pattern was similar to the observed maximal specific increase in bradykinin binding with confluency. Together these results demonstrate the presence of bradykinin receptors in human gingival fibroblasts; these receptors are coupled to signal transduction mechanisms involving the PLC, PLA2, and tyrosine kinase effector systems, all of which require extracellular calcium to achieve maximal activation.
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PMID:Bradykinin receptors and signal transduction pathways in human fibroblasts: integral role for extracellular calcium. 768 36

Galanin has numerous effects on gastrointestinal smooth muscle. However, because of the lack of specific inhibitors, it is not known which are physiological and which are pharmacological. This study investigates the ability of two chimeric galanin analogs, [# 1-galantide = (M-15) = [galanin (1-13)-substance P(5-11)] and #2-M-35[galanin(1-13)bradykinin (2-9)], which were recently reported to function as galanin-receptor antagonists in the CNS, to interact with galanin receptors on rat jejunal muscle strips or dispersed smooth muscle cells from guinea pig stomach. In both systems each chimeric analog had agonist activity and was as efficacious as galanin. Cross-desensitization experiments demonstrated that in the jejunal muscle strips, both chimeric analogs were causing muscle contraction by interacting with the galanin receptor. In dispersed smooth muscle cells, galanin, as well as each chimeric analog, caused muscle relaxation, whereas substance P and bradykinin both caused muscle contraction. Each chimeric analog was equipotent to galanin in inhibiting binding of 125I-galanin, and there was close agreement between their abilities to occupy the galanin receptor and cause relaxation. Each chimeric analog also activated adenylate cyclase and increased cAMP characteristic of relaxants. These studies demonstrate these chimeric analogs will not be useful for defining the physiological role of galanin in altering gastrointestinal motility, because they function as full galanin-receptor agonists instead of as galanin-receptor antagonists.
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PMID:Chimeric galanin analogs that function as antagonists in the CNS are full agonists in gastrointestinal smooth muscle. 768 5

Bradykinin and phorbol 12-myristate 13-acetate stimulate adenylate cyclase activity in serum-depleted cultured airway smooth muscle via a protein kinase C (PKC)-dependent pathway. The probable target is the type II adenylate cyclase, which can integrate coincident signals from both PKC and Gs. Therefore, activation of Gs (by cholera-toxin pre-treatment) amplified the bradykinin-stimulated cyclic AMP signal and concurrently attenuated the partial activation of extracellular-signal-regulated kinase-2 (ERK-2) by bradykinin. We have previously demonstrated that, in order to induce full activation of ERK-2 with bradykinin, it is necessary to obliterate PKC-stimulated cyclic AMP formation. We concluded that the cyclic AMP signal limits the magnitude of ERK-2 activation [Pyne, Moughal, Stevens, Tolan and Pyne (1994) Biochem. J. 304, 611-616]. The present study indicates that the bradykinin-stimulated ERK-2 pathway is entirely cyclic AMP-sensitive, and suggests that coincident signal detection by adenylate cyclase may be an important physiological route for the modulation of early mitogenic signalling. Furthermore, the direct inhibition of adenylate cyclase activity enables bradykinin to induce DNA synthesis, indicating that the PKC-dependent activation of adenylate cyclase limits entry of cells into the cell cycle. These studies suggest that the mitogenicity of an agonist may be governed, in part, by its ability to stimulate an inhibitory cyclic AMP signal pathway in the cell. The activation of adenylate cyclase by PKC appears to be downstream of phospholipase D. However, in cells that were maintained in growth serum (i.e. were not growth-arrested), bradykinin was unable to elicit a PKC-stimulated cyclic AMP response. The lesion in the signal-response coupling was not at the level of either the receptor or phospholipase D, which remain functionally operative and suggests modification occurs at either PKC or adenylate cyclase itself. These studies are discussed with respect to the cell signal regulation of mitogenesis in airway smooth muscle.
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PMID:Adenylate cyclase, cyclic AMP and extracellular-signal-regulated kinase-2 in airway smooth muscle: modulation by protein kinase C and growth serum. 770 66

In guinea pig ileum membranes, the pre-stimulated adenylate cyclase activity was dose-dependently inhibited by picomolar concentrations of bradykinin exhibiting an apparent IC50 value of approximately 30 pM. At nanomolar bradykinin concentrations (> 1 nM) this effect was attenuated. The inhibition of ileal adenylate cyclase was completely prevented by both the bradykinin B2 receptor antagonist Hoe 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin) and pertussis toxin. The potency of bradykinin to inhibit ileal adenylate cyclase considerably correlates with a binding site with picomolar affinity for bradykinin. In addition, a second site was constantly found displaying nanomolar binding affinity for bradykinin. The occurrence of two independent bradykinin B2 receptors in guinea pig ileum membranes is further supported by three other lines of evidence: bradykinin stimulates [35S]GTP[S] (guanosine 5'-O-[3-thiotriphosphate]) binding to guinea pig ileum membranes in a biphasic manner with EC50 values which correspond to the affinities of both sites. In binding studies, the high-affinity site cannot be transformed into the low-affinity site in the presence of Gpp[NH]p (5'-guanylylimidodiphosphate). The specific binding of [3H]bradykinin to guinea pig ileum membranes was also biphasically inhibited by increasing concentrations of Gpp[NH]p. Thus, our results favour the existence of two separate bradykinin B2 receptors with different signal transduction pathways in guinea pig ileum membranes: one receptor with picomolar affinity for bradykinin which inhibits adenylate cyclase via a pertussis toxin-sensitive G protein of probably the Gi2 type and the other receptor with nanomolar affinity for bradykinin which might be responsible for bradykinin-induced stimulation of phosphoinositide hydrolysis.
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PMID:Bradykinin inhibits adenylate cyclase activity in guinea pig ileum membranes via a separate high-affinity bradykinin B2 receptor. 770 66

Receptor subtypes and intracellular signaling events involved in bradykinin-evoked contraction of colonic circular muscle are unknown. We studied the roles of inositol trisphosphate (IP3) and cyclic AMP generation and the selectivity for B1 and B2 receptors in guinea pig colon. Bradykinin induced concentration-dependent contraction of circular muscle strips with an EC50 of 2 x 10(-8) M that was inhibited by the B2 antagonist D-Argo-(Hyp3,Thi5,8,D-Phe7)-bradykinin but not the B1 antagonist des-Arg9-[Leu8]bradykinin. The B1 agonist des-Arg9-bradykinin did not evoke contraction or relaxation. Bradykinin induced concentration-dependent shortening of isolated myocytes from circular muscle with an EC50 of 2 x 10(-11) M that was inhibited by the B2 but not the B1 antagonist, confirming the myogenic nature of the bradykinin receptors. Persistence of myocyte contraction in a calcium-free medium with EGTA confirmed the lack of dependence on extracellular calcium. In colon muscle tissue, bradykinin evoked concentration-dependent IP3 generation with an EC50 of 10(-7) M and a maximal level of 58 +/- 17 pmol/mg of protein at 10(-4) M that was inhibited by the B2 but not the B1 antagonist. Bradykinin, acting on B2 receptors, inhibited cyclic AMP formation after forskolin (10(-5) M) with an EC50 of 3 x 10(-8) M and maximal inhibition of 48% at 10(-5) M. In conclusion, bradykinin induces colon muscle contraction via myogenic non-B1 receptors, which are likely of the B2 subtype, with phosphoinositide turnover activation and adenylate cyclase inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bradykinin acting on B2 receptors contracts colon circular muscle cells by IP3 generation and adenylate cyclase inhibition. 771 87

Human tracheal epithelial cells in primary culture respond to different receptor agonists with different peak intracellular calcium concentrations. From resting concentration 138 +/- 13 nM, bradykinin (0.1 microM) produces an increase to a maximum of 835 +/- 195 nM, histamine (10 microM) to 352 +/- 51 nM, and ATP (5-500 microM) to more than 1500 nM. Nine of 14 cultures also responded to isoproterenol (10 microM), though with a smaller increase, to 210 +/- 29 nM. A response was observed with isoproterenol, and epinephrine, but not norepinephrine, phenylephrine or methoxamine, was inhibited by propranolol but not phentolamine, and so this appeared to be a beta-adrenergic response. However, no response could be detected to adenosine, prostaglandin E2 or forskolin, agents that activate adenylate cyclase, or to permeant analogs of cAMP (CPT-cAMP or db-cAMP). The intracellular calcium response to isoproterenol did not follow either the time-course or the desensitization pattern of the cAMP response. Thus, this response to isoproterenol is not mediated by cAMP. No relation was demonstrated between cAMP production by other agonists and the response of intracellular calcium. Pretreatment with agents that increase cAMP did not affect the calcium responses to ATP or bradykinin. Thus, cAMP does not regulate intracellular calcium concentration in human tracheal epithelial cells. The variation in peak intracellular calcium responses to various agonists may be explained by the presence of multiple second messengers (other than cAMP), multiple intracellular pools of calcium, or cell heterogeneity. The agonists tested had the same relative potency in cells from patients with cystic fibrosis as in non-cystic fibrosis cells.
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PMID:cAMP does not regulate [Ca2+]i in human tracheal epithelial cells in primary culture. 787 56

1. Bradykinin and related kinins possess two different types of action (consisting of relaxation and contraction) in the isolated rat duodenum via their specific receptors. However, the mechanisms of these actions have not been fully elucidated. The present study was undertaken to investigate the effects of the agents affecting cyclic nucleotide metabolism on bradykinin-induced relaxations and on bradykinin- and des-Arg9-bradykinin-induced contractions. 2. Des-Arg9-bradykinin, B1 receptor agonist, and high concentrations of bradykinin elicited dose-dependent contractile responses in the rat duodenum, while low concentrations of bradykinin caused a dose-dependent relaxation in this tissue. 3. Nicotinic acid, an inhibitor of adenylate cyclase, inhibited the relaxation of rat duodenum induced by bradykinin at low concentrations in a non-competitive manner. However, the inhibitory efficacy of nicotinic acid against bradykinin was limited by 39.9% and this inhibition was not further increased by higher concentrations of nicotinic acid up to 10(-3) M. 4. Imidazole, an activator of cyclic nucleotide phosphodiesterase, caused a slight inhibition of the relaxant responses to low concentrations of bradykinin and of the contractile responses to des-Arg9-bradykinin and high concentrations of bradykinin in isolated rat duodenum. These inhibitions were also limited in efficacies and not increased by higher concentrations of imidazole. 5. Methylene blue, an agent that inhibits soluble guanylate cyclase, suppressed the contractions of rat duodenum induced by des-Arg9-bradykinin and high concentrations of bradykinin in a non-competitive manner. Again, these inhibitions were limited and further increase in the inhibitory efficacy was not observed in spite of increasing the methylene blue concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of the agents affecting cyclic nucleotide metabolism on the bradykinin- and des-Arg9-bradykinin-induced relaxations and contractions in isolated rat duodenum. 789 50


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