Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have assessed the effects of endothelin-1 (ET-1) on transmembrane signaling in adult rat ventricular myocytes. ET-1 stimulates phosphoinositide hydrolysis with an EC50 of 0.3-0.8 nM. This stimulation is linear for up to 30 min in the presence of a protease inhibitor, is additive with the effects of other stimulators of phosphoinositide hydrolysis, is not inhibited by the Ca2+ entry blocker, nifedipine, and is insensitive to pertussis toxin. ET-1 also reduces cyclic AMP production in myocytes in response to isoproterenol and forskolin (EC50, 1 nM). This cyclic AMP-lowering effect of ET-1 is sensitive to pertussis toxin, can be demonstrated directly in assays of adenylate cyclase activity of myocyte membranes, and seems to be mediated by Gi. These data indicate that the effects of endothelin on adult cardiac myocytes involve multiple signaling pathways, including enhanced activity of the inositol phosphate pathway and a decrease in cyclic AMP-mediated responses, neither of which seems likely to account for the positive contractile effects of endothelin.
 ...
PMID:Endothelin inhibits adenylate cyclase and stimulates phosphoinositide hydrolysis in adult cardiac myocytes. 131 4

To clarify a possible involvement of the vasoconstrictive peptide endothelin in the regulation of endothelial cell-mediated fibrinolytic system, confluent cultures of vascular endothelial cells from human umbilical vein were incubated in serum-free medium in the presence of endothelin-1 at 100 nM and below, and tissue plasminogen activator antigen (t-PA:Ag) in the medium was determined by enzyme immunoassay. Endothelin-1 at 1 nM and above significantly decreased the release of t-PA:Ag from the endothelial cells after a 24 h incubation. The t-PA:Ag release was also decreased by either endothelin-2 or endothelin-3 at 10 nM. The activity of lactate dehydrogenase in the medium was not changed by endothelin-1 at 100 nM and below, suggesting that the peptide did not cause nonspecific cell damage. The decrease in the t-PA:Ag release induced by endothelin-1 occurred in the presence or absence of 8-bromo cyclic AMP, which is an active congener of cyclic AMP; 3-isobutyl-1-methylxanthine, which is an inhibitor of phosphodiesterase; and forskolin, which is a stimulator of adenylate cyclase. These results strongly indicated that cyclic AMP which is known to down-regulate t-PA:Ag release was not involved in the endothelin-1 effect. However, endothelin-1 failed to decrease the t-PA:Ag release in the presence of either calcium ionophore A23187 or EGTA; the ionophore itself markedly decreased the release. The cytosolic calcium accumulation was significantly increased by endothelin-1. These results suggest that endothelin-1 decreases the release of t-PA:Ag from human endothelial cells through an excess accumulation of intracellular, especially cytosolic which would be mediated by an extracellular, calcium-dependent mechanism.
 ...
PMID:Endothelin modulation of tissue plasminogen activator release from human vascular endothelial cells in culture. 137 54

The present study was undertaken to examine the effects of arginine vasopressin (AVP) and endothelin-1 (ET-1) on cytosolic free Mg2+ ([Mg2+]i) in cultured rat vascular smooth muscle cells (VSMC). [Mg2+]i was measured using the fluorescence indicator dye mag-fura-2. AVP and ET-1 at a concentration of 1 x 10(-9) M or higher induced the mobilization of [Mg2+]i and cytosolic free Ca2+ ([Ca2+]i) in a dose-dependent manner in rat VSMC. Atrial natriuretic peptide and sodium nitroprusside producing cellular guanosine 3',5'-cyclic monophosphate did not affect [Mg2+]i and [Ca2+]i. A diterpene activator of adenylate cyclase, forskolin, also did not alter [Mg2+]i and [Ca2+]i. The removal of extracellular Mg2+ enhanced the AVP-mobilized [Ca2+]i and did not change the AVP-mobilized [Mg2+]i. The Ca(2+)-free and nominally Mg2+/Ca(2+)-free states decreased the AVP-mobilized [Mg2+]i and [Ca2+]i. The Na(+)-free state enhanced the sustained, but not peak, level of the AVP-mobilized [Mg2+]i. These results indicate that AVP and ET-1 mobilize [Mg2+]i mediated through their intracellular second messenger [Ca2+]i and independent of extracellular Mg2+. Also, an increase in [Mg2+]i is indicated to stimulate the Na(+)-Mg2+ exchange to increase cellular Mg2+ efflux.
 ...
PMID:Cellular mechanisms of vasopressin and endothelin to mobilize [Mg2+]i in vascular smooth muscle cells. 141 72

The authors investigated the effects of endothelin-1 (ET1) on inositol trisphosphate (IP3) production, 1, 2-diacylglycerol (DAG) formation, measured as phosphatidic acid (PA), cAMP formation, and contraction in iris sphincter of different mammalian species. They found that ET1 is a potent agonist for IP3 production, DAG formation, and contraction in rabbit, dog, cat, and pig iris sphincters, and for cAMP formation in all species that were investigated--rabbit, dog, cat, pig, bovine, monkey, and human sphincters. In the bovine model, ET1 induced cAMP formation in a dose-dependent manner, with an EC50 of 28 nM. This is the first report that showed an effect of the peptide on the adenylate cyclase system. In rabbit sphincter, ET1 induced a significant increase in IP3 production by 30 sec and reached a 6-fold level more than control within 1 and 5 min. ET1-stimulated IP3 production is dose dependent with an EC50 of 45 nM, this value is about 100- and 56-fold lower than those we reported for substance P and carbachol, respectively. ET1 also increased 32P labeling of PA more than 6-fold; and in rabbit sphincter, ET1 is a more potent agonist in contracting the sphincter than in contracting the dilator (the EC50 values for sphincter and dilator were 46 and 120 nM, respectively). L-type Ca2+ channels are not involved in IP3- and contraction responses because several blockers of these channels did not affect the ET1-induced responses, implying that in the iris sphincter, ET1 elicits the physiologic response through the G protein activation of phospholipase C and/or adenylate cyclase and not through the activation of voltage-dependent Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Species differences in the effects of endothelin-1 on myo-inositol trisphosphate accumulation, cyclic AMP formation and contraction of isolated iris sphincter of rabbit and other species. 164 47

C-type natriuretic peptide and sodium nitroprusside, a nitric oxide donor molecule, induced large increases in cyclic GMP formation in cultured rat brain capillary endothelial cells. Isoproterenol, a potent agonist of adenylate cyclase, potentiated the actions of C-type natriuretic peptide and of sodium nitroprusside. These actions were not observed in the presence of isobutylmethylxanthine and were mimicked by forskolin. Endothelin-1 had no action on basal cyclic GMP levels. It reduced cyclic GMP formation induced by C-type natriuretic peptide and sodium nitroprusside by about 50%. These actions involved an ETA receptor subtype and a Ca(2+)-dependent and protein kinase C-independent mechanism. Finally, increasing cyclic GMP slightly prolonged intracellular Ca2+ transients induced by endothelin-1. The results suggest the presence of extensive cross talk among cyclic AMP, cyclic GMP, and Ca(2+)-dependent mechanisms in endothelial cells of brain microvessels. The relevance of the results to the regulation of the blood-brain barrier permeability is discussed.
 ...
PMID:Cross talk among cyclic AMP, cyclic GMP, and Ca(2+)-dependent intracellular signalling mechanisms in brain capillary endothelial cells. 751 50

Endothelial cells are central in fibrinolysis because of their high production of both activators (t-PA, uPA) and inhibitors (PAI-1). The t-PA and PAI-1 synthesis could be regulated by signals transduction at several cellular levels. The purpose of this in vitro study, on cultured endothelial cells, was to explore the receptor/second messenger regulation of the t-PA and PAI-1 synthesis. Quiescent confluent human umbilical vein endothelial cells, cultured in passage 1, were exposed to different test substances. Samples from the conditioned medium were collected after 16 and 24 h and analysed for t-PA and PAI-1 antigen. All data presented were related to the data from control dishes (= 100%), in the same experiment. The results from the present study (mean +/- 95% confidence interval) demonstrated the following. (1) Forskolin, with a documented direct cAMP-inducing effect, decreased the basal PAI-1 production to 61 +/- 15%, and Na-nitroprusside, with a documented cGMP-inducing effect, increased the basal PAI-1 production to 141 +/- 38% without affecting the basal t-PA production. The surface receptor agonists isoprenalin or ephedrine, which indirectly affect adenylate cyclase, had no effect on t-PA or PAI-1 production. (2) Phorbolester (PMA), which directly activates proteinkinase C (PKC), increased the basal t-PA and PAI-1 production to 350 +/- 71%, and 163 +/- 35% respectively. (3) Thrombin, but not endothelin-1 (ET-1), increased the basal t-PA and PAI-1 production to 195 +/- 34% and 136 +/- 18%, respectively, indicating an PKC-mediated thrombin effect.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Complex intracellular signal transduction regulates tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) synthesis in cultured human umbilical vein endothelium. 756 35

The steroidogenic activity of the Leydig cell is regulated by glycoprotein and peptide hormones with the potential to activate both adenylate cyclase and phospholipase C. Although the control of androgen production by LH is clearly mediated by cAMP, the extent to which Ca(2+)-mobilizing stimuli control Leydig cell function is less well defined. The basal level of intracellular calcium ([Ca2+]i) in adult rat Leydig cells was 70-160 nM and was unaffected by high K+ or the dihydropyridine calcium channel agonist, Bay K 8644. These findings are consistent with the absence of voltage-sensitive calcium channels in the Leydig cell. In addition, no increase in [Ca2+]i was observed in cells treated with LH, CRF, and serotonin. However, both GnRH and endothelin-1 (ET-1) induced rapid and transient elevations of [Ca2+]i that were not associated with a sustained plateau phase and were unaffected by removal of Ca2+ from the incubation medium. The amplitude of the [Ca2+]i response was not altered by increasing concentrations of GnRH and ET-1, but the number of responsive cells increased progressively to a maximum of about 30% of the Leydig cell population. The calcium-mobilizing actions of GnRH and ET-1 were abolished by the GnRH and ETA receptor antagonists, [Dp-Glu1,D-Phe2,D- Trp3,6]GnRH and BQ-123, respectively. The majority of the cells expressed solely GnRH or ETA receptors, and about 10% expressed both receptors. GnRH-induced Ca2+ responses were observed almost exclusively in medium-sized Leydig cells, whereas ET-induced responses were most frequent in large Leydig cells. These data demonstrate that single Leydig cells expressing GnRH and ETA receptors exhibit monophasic [Ca2+]i responses that are activated in an all-or-none fashion. Such transient Ca2+ signaling may trigger short term cellular responses or could modulate the actions of gonadotropins acting through the cAMP signaling pathway.
 ...
PMID:Calcium signaling in single rat Leydig cells. 762 78

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.
 ...
PMID:Effects of vasoactive substances and cAMP related compounds on adrenomedullin production in cultured vascular smooth muscle cells. 764 78

The effects of endothelin-1 (ET-1) on whole-cell cardiac PKA-dependent Cl- currents (ICl) were investigated using patch clamp techniques. ET-1 inhibited the isoproterenol-induced ICl with a half-maximally effective concentration of approximately 1 nM. ET-1 also inhibited the forskolin-induced current in a similar concentration range. The effects of ET-1 were abolished by pre-treatment of the cells with pertussis toxin. Since ET-1 was ineffective at inhibiting the ICl induced by internal dialysis with cyclic AMP, it is unlikely that the Gi-protein had a direct effect on channel gating or phosphorylation of the channel by PKA. It is concluded that ET-1 inhibited the cardiac PKA-dependent ICl by attenuating activation of adenylate cyclase and that this effect was mediated by a pertussis toxin-sensitive G-protein, presumably Gi.
 ...
PMID:The effects of endothelin-1 on the PKA-dependent Cl- current in the heart. 775 29

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.
 ...
PMID:Inhibition of endothelin production by adrenomedullin in vascular smooth muscle cells. 776 61


1 2 3 4 Next >>