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)

The present study investigated the effect of adrenomedullin, a novel vasorelaxant peptide, on the migration of cultured rat vascular smooth muscle cells (SMCs) by using the Boyden-chamber method. Fetal calf serum (FCS) and platelet-derived growth factor (PDGF)-BB strongly stimulated SMC migration. Adrenomedullin clearly inhibited SMC migration stimulated with 5% and 10% FCS in a concentration-dependent manner. The migration induced by 10 and 25 ng/mL PDGF-BB was also inhibited by adrenomedullin in a concentration-dependent manner. Inhibition by adrenomedullin of FCS- and PDGF-induced SMC migration was paralleled by an increase in the cellular level of cAMP. In fact, the percent increase in cAMP level was strongly correlated with the percent decrease in migration activity of SMCs after treatment with adrenomedullin. 8-Bromo cAMP, a cAMP analogue, reproduced the inhibition by adrenomedullin of FCS- and PDGF-induced SMC migration. An activator of adenylate cyclase, forskolin, also reduced FCS- and PDGF-induced SMC migration. These data indicate that adrenomedullin inhibits the migration of SMCs stimulated with FCS and PDGF, probably through a cAMP-dependent process. On the basis of these results and the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, adrenomedullin may play a role as a local antimigration factor in some pathophysiological states.
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PMID:Adrenomedullin as a novel antimigration factor of vascular smooth muscle cells. 755 10

Accumulation of the intracellular cyclic AMP (cAMP) was measured in cultured endothelial cells of the human umbilical vein following the incubation with adrenomedullin, a newly discovered hypotensive peptide, to determine the presence of specific receptors for adrenomedullin. Adrenomedullin increased the intracellular cAMP in a dose-dependent fashion in the endothelial cells, and the EC50 value was as low as 10(-9) M. Calcitonin gene-related peptide (CGRP) that has a homology to adrenomedullin in its amino-acid sequence also increased the intracellular cAMP with an EC50 value greater than 10(-7) M. The effect of CGRP was attenuated in the presence of CGRP-(8-37), a CGRP receptor antagonist. However, CGRP-(8-37) had no effect on the cAMP accumulation by adrenomedullin. These findings indicate that the cultured endothelial cells of human umbilical vein possess specific adrenomedullin receptors coupled with the adenylate cyclase activity that may have little affinity with CGRP.
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PMID:Receptors for adrenomedullin in human vascular endothelial cells. 762 13

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

The effect of human adrenomedullin on cerebral circulation was investigated in dogs in vivo and in vitro. Bolus administration of adrenomedullin or its homologous peptides, calcitonin gene-related peptide (CGRP) and amylin, into the vertebral artery induced a dose-dependent increase in vertebral blood flow. The potencies of adrenomedullin and CGRP were similar and approximately 100 times more than that of amylin. The effects of adrenomedullin and CGRP were inhibited by CGRP8-37, an antagonist of CGRP. In contrast to substance P, adrenomedullin did not induce an increase in blood flow after prior administration of CGRP. Pretreatment with either NG-nitro-L-arginine methyl ester or indomethacin did not affect the adrenomedullin-induced increase in blood flow. Intracisternal administration of adrenomedullin induced dilation of the basilar and other major cerebral arteries in a dose-dependent manner, accompanied by an increase in the concentration of cyclic AMP in the cerebrospinal fluid. Adrenomedullin also induced relaxation of isolated basilar and middle cerebral arterial rings. These data suggest that adrenomedullin induces vasodilation of cerebral arteries and an increase in vertebral blood by acting at CGRP receptors positively coupled to adenylate cyclase, and that these effects are not dependent on nitric oxide or prostaglandin formation.
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PMID:Effects of adrenomedullin, calcitonin gene-related peptide, and amylin on cerebral circulation in dogs. 767 75

Adrenomedullin recently has been found to potently stimulate cAMP formation in cultured rat vascular smooth muscle cells (VSMCs). In the present study, we examined the effect of adrenomedullin on the production of a vasoconstrictive and growth-promoting peptide, endothelin-1, after stimulation with a clotting enzyme, thrombin, and a potent mitogen, platelet-derived growth factor (PDGF), in cultured rat VSMCs. Thrombin and PDGF stimulated endothelin-1 production in a dose-dependent manner. Rat adrenomedullin significantly inhibited thrombin- and PDGF-stimulated endothelin-1 production in a dose-dependent manner between 10(-7) and 10(-9) mol/L. Inhibition by rat adrenomedullin of thrombin- and PDGF-stimulated endothelin-1 production was paralleled by an increase in the cellular level of cAMP. Human adrenomedullin also inhibited thrombin- and PDGF-stimulated endothelin-1 production and increased cAMP levels. The addition of 8-bromo-cAMP, a cAMP analogue, reduced thrombin- and PDGF-induced endothelin-1 production. Furthermore, forskolin, a potent activator of adenylate cyclase, reduced thrombin- and PDGF-induced endothelin-1 production. In contrast, basal production of endothelin-1 was not altered by rat or human adrenomedullin. These results indicate that adrenomedullin inhibits not basal but thrombin- and PDGF-induced ET-1 production in cultured VSMCs probably through a cAMP-dependent process. Taken together with the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, adrenomedullin may modulate vascular tone as a paracrine regulator partially through the inhibition of VSMC endothelin-1 production in some pathophysiological states.
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PMID:Inhibition of endothelin production by adrenomedullin in vascular smooth muscle cells. 776 61

The present study was designed to examine the effect of synthetic adrenomedullin (AM), a novel vasorelaxant peptide originally isolated from human pheochromocytoma, on intracellular cyclic adenosine monophosphate (cAMP) formation in cultured rat mesangial cells. The effect of AM on cAMP formation in rat mesangial cells was compared with its effect in cultured rat vascular smooth muscle cells. cAMP levels were determined by radioimmunoassay after stimulation for 30 minutes with different concentrations (10(-10) to 10(-7) mol/L) of rat and human AM. Rat and human AM concentration-dependently (10(-9) to 10(-7) mol/L) stimulated cAMP formation in cultured mesangial cells. This stimulatory effect of rat AM was significantly greater than human AM. The stimulatory effect of rat AM in mesangial cells was significantly weaker than its potency in vascular smooth muscle cells. These preliminary data suggest that mesangial cells, as well as vascular smooth muscle cells, possess AM receptors functionally coupled to adenylate cyclase.
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PMID:Stimulation of cyclic adenosine monophosphate formation by the novel vasorelaxant peptide adrenomedullin in cultured rat mesangial cells. 785 53

Vascular smooth muscle cells (VSMC) from rat aorta possess specific receptors for a novel potent vasorelaxant peptide, adrenomedullin (AM). To elucidate its receptor coupling to guanine nucleotide-binding stimulatory protein and the structural requirement of the AM molecule to its vascular receptors, we have studied the effects of guanine nucleotides on [125I]human (h) AM binding and adenylate cyclase activity in cultured rat VSMC, and the effects of various synthetic hAM analogs on [125I]hAM binding and the cAMP response. Guanosine 5'-O-(3-thiotriphosphate) dose dependently inhibited [125I]hAM binding to rat VSMC membranes. hAM stimulated adenylate cyclase activity, and its effect was additive with GTP. hAM-induced cAMP formation was abrogated by pretreatment with cholera toxin, but not by that with pertussis toxin. Intact hAM-(1-52)-NH2 and N-terminal truncated derivatives [hAM-(13-52)-NH2, hAM-(16-52)-NH2] almost equally inhibited [125I]hAM binding and stimulated cAMP formation, whereas removal of C-terminal Tyr52 residue [hAM-(1-51)-NH2] remarkably decreased receptor-binding activity and the cAMP response. The effects of hAM-(1-52)-OH, hAM-(1-51)-OH, and a linear hAM analog ([carbamoylmethyl-Cys16,21]hAM-NH2) were far less potent on receptor binding and the cAMP response than that of hAM-(1-52)-NH2. The C-terminal fragment [hAM-(33-52)-NH2] and the N-terminal fragment [hAM-(1-10)-OH] had neither receptor-binding nor adenylate cyclase activity. hAM-(22-52)-NH2 had no agonistic effect, but showed an antagonistic effect on the hAM-induced cAMP response. These data suggest that vascular AM receptors are functionally coupled to adenylate cyclase via guanine nucleotide-binding stimulatory protein. Studies of the structure-activity relationship of hAM revealed that the cyclic structure formed by the disulfide bridge and amidation of the C-terminal residue of the AM molecule are critical for receptor binding and subsequent cAMP generation and suggest that the C-terminal fragment hAM-(22-52)-NH2 may be an antagonist for vascular AM receptors.
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PMID:Structure-activity relationship of adrenomedullin, a novel vasodilatory peptide, in cultured rat vascular smooth muscle cells. 798 31

The effects of synthetic rat adrenomedullin (rAM), a novel vasorelaxant peptide originally isolated from human pheochromocytoma, on receptor binding and cAMP generation were studied in cultured rat vascular smooth muscle cells (VSMC). A binding study using [125I]rAM revealed the presence of a single class of high-affinity (Kd 1.3 x 10(-8) M) binding sites for rAM in VSMC. The apparent Ki of rat calcitonin gene-related peptide (rCGRP) was 3 x 10(-7) M. Affinity labeling of VSMC membranes with [125I]rAM revealed two distinct labeled bands with apparent molecular weights of 120 and 70 kDa, both of which were abolished by excess unlabeled rAM or rCGRP, rAM stimulated cAMP formation with an approximate EC50 of 10(-8) M, the effect of which was additive with isoproterenol, but not with rCGRP. The rAM-induced cAMP response was unaffected by propranolol, indomethacin, or quinacrine, but inhibited by a CGRP receptor antagonist, human CGRP[8-37]. These data suggest that VSMC possesses specific AM receptors functionally coupled to adenylate cyclase with which CGRP interacts.
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PMID:Specific receptors for adrenomedullin in cultured rat vascular smooth muscle cells. 813 50

Adrenomedullin has recently been isolated from human pheochromocytoma. We designed the present study to examine the effect of adrenomedullin on the production of the vasoconstrictive and growth-promoting peptide endothelin-1 (ET-1) after stimulation with platelet-derived growth factor (PDGF) in cultured rat glomerular mesangial cells. PDGF stimulated ET-1 production in a concentration-dependent manner. Rat adrenomedullin inhibited this stimulated ET-1 production in a concentration-dependent manner between 10(-7) and 10(-8) mol/L. Rat adrenomedullin also increased the cellular level of cAMP in a concentration-dependent manner between 10(-7) and 10(-8) mol/L. Human adrenomedullin was less effective than rat adrenomedullin with respect to inhibiting ET-1 production and increasing cAMP levels. The addition of 8-bromo-cAMP (10(-3) and 10(-4) mol/L) reduced PDGF-induced ET-1 production. Furthermore, forskolin (10(-4) and 10(-5) mol/L), an activator of adenylate cyclase, reduced PDGF-induced ET-1 production. In contrast, the basal production of ET-1 was not significantly altered by rat and human adrenomedullin. These results indicate that adrenomedullin inhibits PDGF-induced ET-1 production in cultured rat mesangial cells, probably through a cAMP-dependent process.
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PMID:Interaction of adrenomedullin and platelet-derived growth factor on rat mesangial cell production of endothelin. 861 21

We have previously demonstrated specific binding sites for adrenomedullin, a novel member of the calcitonin family of peptides, in rat muscles. It is unclear whether these receptors are vascular or muscular. Receptors for the structurally similar calcitonin gene-related peptide (CGRP) are present on myocytes and might be involved in the regulation of myocyte glucose metabolism and control by motor neurons. We investigated whether adrenomedullin binding sites were present on L6 myocytes. Specific [125I]adrenomedullin binding sites were demonstrated where adrenomedullin competed with an IC50 of 0.22 +/- 0.04 nM (mean +/- S.E.M.) and a concentration of binding sites (Bmax) of 0.95 +/- 0.19 pmol/mg of protein (mean +/- S.E.M.). CGRP and the specific CGRP receptor antagonist CGRP(8-37) competed weakly at this site (IC50 > 10 and 601 +/- 298 nM respectively). Binding studies with [125I]CGRP revealed a binding site for CGRP (IC50 = 0.13 +/- 0.01 nM; Bmax = 0.83 +/- 0.10 pmol/mg of protein) where both CGRP(8-37) and adrenomedullin competed with [125I]CGRP with IC50 values of 1.15 +/- 0.12 and 8.68 +/- 0.98 nM respectively. Chemical cross-linking showed the CGRP and adrenomedullin binding site-ligand complexes to have approximate molecular masses of 82 and 76 kDa respectively. Both CGRP and adrenomedullin increased adenylate cyclase activity with similar potencies. In both cases adenylate cyclase activation was blocked by CGRP(8-37). Stimulation with 10 nM adrenomedullin or CGRP caused an increase in the percentage of total activated cellular cAMP-dependent protein kinase from 38% in resting cells to 100% and 98% respectively. Therefore in L6 cells adrenomedullin can bind to CGRP receptors, activating adenylate cyclase and cAMP-dependent protein kinase.
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PMID:A rat skeletal muscle cell line (L6) expresses specific adrenomedullin binding sites but activates adenylate cyclase via calcitonin gene-related peptide receptors. 876 78


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