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)

Synergistic interaction between ADP, adrenaline, 5-hydroxytryptamine (5HT) and [8-arginine]vasopressin is not observed for the aggregatory response of aspirin-treated human platelets when this response is estimated directly from the decrease in the number of single platelets in the suspension. This finding is in marked contrast with prior reports of synergistic interaction between these agonists when the rate and extent of the aggregometer response is estimated from the increase in the light transmittance of the suspension, using a platelet aggregometer. We propose that the apparent synergistic response detected using the aggregometer results from the inability of this instrument to respond during the initial phase of aggregation. Significant synergistic interaction is observed for the increase in cytosolic [Ca2+] induced by addition of the ADP/5HT and, to a lesser extent, of the ADP/vasopressin agonist pairs as compared with that caused by addition of the individual agonists. This effect is not, however, typical of the system since increases in cytosolic [Ca2+] induced by addition of the ADP/thrombin or 5HT/vasopressin agonist pairs are no greater than the sum of the responses to these agonists added separately. Addition of collagen prior to ADP or 11,9-epoxymethanoprostaglandin H2 (U46619) fails to enhance the increase in cytosolic [Ca2+] induced by these latter agonists. Adrenaline, when added prior to non-saturating concentrations of U46619, thrombin, vasopressin or ADP, significantly enhances the increase in cytosolic [Ca2+] induced by these agonists in platelets suspended in media containing less than 0.1 microM or 1 mM Ca2+. However, adrenaline fails to enhance the increase in cytosolic [Ca2+] induced by the divalent cation ionophore, ionomycin. Enhancement by adrenaline of Ca2+ influx induced by U46619, thrombin and ADP has been shown by using Mn2+ as probe. Adrenaline also enhances the extent of [3H]5HT secretion induced by U46619, thrombin and vasopressin but fails to increase that induced by ADP in this aspirin-treated preparation. These results are in part consistent with the postulate that adrenaline, acting via an alpha 2-adrenoceptor, modulates receptor--phospholipase-C coupling. However, such modulation does not appear to involve inhibition of adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Synergistic responses in human platelets. Comparison between aggregation, secretion and cytosolic Ca2+ concentration. 349 Sep 77

The effect of forskolin on collagen production in osteoblasts was investigated by using clonal osteoblastic MC3T3-E1 cells cultured in a-minimum essential medium containing 0.1% bovine serum albumin. Forskolin increased the adenylate cyclase activity in membranes pelleted from homogenates of the cell line in a dose-dependent manner. The drug caused a 13-fold stimulation at 10(-4) M, indicating that the compound directly acts on adenylate cyclase, leading to an increase in the intracellular cAMP content of the cells. Collagen accumulation in the cultures was elevated by one-day treatment with 5 X 10(-5) M forskolin to about twice that in the controls. The stimulation was mainly due to an elevation in collagen synthesis but not to an inhibition of intracellular collagen degradation because forskolin dose-dependently increased collagen synthesis; it also significantly increased the amount of low-molecular-weight hydroxyproline found in the cultures. Cells treated with forskolin produced mainly type I collagen, as found in bone matrix in situ, with only small amounts of other types of collagen. Furthermore, forskolin time-dependently inhibited DNA synthesis in the cells, indicating that the increase in type I collagen synthesis by forskolin was not due to stimulated cell proliferation. These results suggest that cAMP is closely linked to the differentiation of osteoblasts in vitro.
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PMID:Effect of forskolin on collagen production in clonal osteoblastic MC3T3-E1 cells. 366 59

The mechanism of inhibition of the vascular-platelet stage of hemostasis by medicinal leech salivary gland secretion was studied. It was shown that the secretion blocks platelet adhesion on the surface of collagens belonging to different genetic classes, inhibits the primary attachment of platelets and completely suppresses their spreading on collagen surface. Whatever its antithrombin activity, the leech secretion inhibits platelet aggregation stimulated by various inductors, e. g., ADP, prostaglandin endoperoxide analog U-46619, Ca2+ ionophore A23187, arachidonic acid. The secretion possessing the antithrombin activity causes a greater inhibition of the thrombin-stimulated aggregation than that devoid of this activity. Leech secretion stimulates adenylate cyclase of platelet membranes in a receptor-mediated fashion and increases the level of cAMP. The active substance is a low molecular weight, thermostable trypsin-resistant fraction of the secretion. Stimulation of adenylate cyclase is not mediated by adenosine receptors. It is supposed that the mechanism of this activating effect involves platelet prostaglandin receptors.
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PMID:[Mechanisms of inhibition of vascular-platelet hemostasis by salivary gland secretion of the medicinal leech Hirudo medicinalis]. 367 59

Confluent monolayers of pig renal papillary collecting tubule (RPCT) cells were formed on Millipore filters coated with collagen. They were clamped in Ussing-type chambers and used to measure short-circuit current (SCC). The monolayers had low potentials (0.1 mV) with the basolateral side positive. Small inward currents flowed under short-circuit conditions. Increases in SCC were obtained following addition of a number of agents. Receptors associated with SCC changes were disposed as follows: for kinins (e.g., lysyl-bradykinin) they were present on both sides of the tissue, while those for arginine vasopressin and norepinephrine were present on the basolateral side only. Epithelia responded to PGE2 added to the apical or basolateral face of the tissue; application to one side prevented the response from the contralateral side. The tissues also responded to forskolin, an activator of adenylate cyclase, with a sustained inward current that was sensitive to furosemide. Similar sustained inward currents were recorded following exposure to 8-bromoadenosine-3',5'-cyclic monophosphate (BrcAMP). Responses to kinins were attenuated by inhibition of fatty acid cyclooxygenase with either indomethacin or piroxicam or by replacing chloride with impermeant ions. If the SCC was first increased with forskolin, BrcAMP, or norepinephrine, the kinin effects on SCC were either abolished or reversed. It is concluded that kinin can cause chloride secretion in RPCT monolayers, possibly via a prostaglandin or a prostaglandin-adenylate cyclase mechanism. Secondary effects of kinin, exposed by first raising tissue cAMP levels, are not precluded.
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PMID:Kinin effects on electrogenic ion transport in primary cultures of pig renal papillary collecting tubule cells. 386 51

The in vitro effects of different lipoprotein fractions (VLDL, LDL and HDL) on human washed platelet aggregation, induced by collagen and thrombin, were evaluated in the presence and absence of PGI2. Although VLDL and LDL increased the platelet aggregation while HDL showed an opposite effect, none of the tested lipoprotein fractions affected the potency of PGI2 as inhibitor of platelet aggregation (IC50). In addition, studies were performed to evaluate the effects of lipoproteins on adenylate cyclase activity in human platelet membranes. The three lipoprotein classes inhibited both basal and PGI2-stimulated adenylate cyclase without affecting the EC50 for PGI2. This inhibitory activity was not specifically elicited by any protein or lipid since neither bovine serum albumin nor a lipid emulsion (Intralipid) displayed any inhibition. The effect on adenylate cyclase elicited by VLDL, LDL and HDL does not seem to be correlated with the activity on platelet aggregation. It is concluded that mediators other than cAMP might be involved in the control of platelet function by lipoproteins.
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PMID:Prostacyclin-lipoprotein interactions. Studies on human platelet aggregation and adenylate cyclase. 389 39

A new antiaggregating chemical, alpha-(p-(fluoren-9-ylidenemethyl)phenyl)-2-piperidineethanol (RMI 10,393), designated FYPE, was found to be an effective inhibitor of platelet aggregation induced by adenosine diphosphate (ADP), thrombin, collagen, or epinephrine. Effects of the antiaggregant on platelets were concentration dependent. Aggregation was prevented by low concentrations of FYPE that produced in the platelet only minor ultrastructural changes consisting of loss of microtubules and of discoid shape. Low levels of FYPE that prevented platelet aggregation had no effect on platelet ATPase activities but did alter clot retraction, the thrombin-induced shift in electrophoretic mobility and platelet cholinesterase activity. Market decrease in ADP release and increase in adenyl cyclase activity were produced by low levels of FYPE. This study provides a model for evaluation of platelet antiaggregating compounds in vitro.
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PMID:Effect of a new antiaggregating chemical on the structure and function of the human platelet. 425 15

The relation of cyclic 3',5'-adenosine monophosphate to platelet function has been studied by investigating the influence of this compound and of its N(6)-2'-0-dibutyryl derivative on platelet aggregation and other aspects of platelet behavior after demonstration of adenyl cyclase activity in disrupted platelets. Dibutyryl cyclic AMP inhibited platelet aggregation induced by ADP, epinephrine, collagen, and thrombin. Cyclic AMP was also inhibitory but was less effective. The platelet "release reaction" was also inhibited; specifically, there was inhibition of the induction of platelet factor 3 activity and of the release of labeled 5-hydroxytryptamine. Platelet swelling produced by ADP was not inhibited. The action of dibutyryl cyclic AMP did not result from contamination with 5'-AMP, nor was it attributable to production of 5'-AMP by plasma enzymes. Dibutyryl cyclic AMP was degraded to 2'-O-monobutyryl cyclic AMP and to cyclic AMP in plasma, but plasma exhibited no cyclic nucleotide phosphodiesterase activity, and the production of 5'-AMP did not occur. The in vitro effects of dibutyryl cyclic AMP were associated with uptake of the compound by platelets. Adenyl cyclase activity of platelet homogenates was demonstrated with production of 9.27 x 10(-11) (+/-2.62 x 10(-11)) mole cyclic AMP per min per 10(10) platelets. The activity was increased by NaF and by prostaglandin PGE(1) and was decreased by epinephrine. The effect of epinephrine was blocked by phentolamine but not by propanolol. Adenyl cyclase activity was also inhibited by collagen, 5-hydroxytryptamine, and thrombin. ADP, dibutyryl cyclic AMP, and cyclic AMP did not alter adenyl cyclase activity. These observations are consistent with the hypothesis that platelet aggregation is favored by a decrease in platelet cyclic AMP and inhibited by an increase in cyclic AMP.
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PMID:Cyclic 3',5'-adenosine monophosphate in human blood platelets. II. Effect of N6-2'-o-dibutyryl cyclic 3',5'-adenosine monophosphate on platelet function. 432 65

The TxA2 receptor antagonist properties of SQ 27,427 [a cyclohexylcarbinol-7-oxabicyclo(2.2.1)heptenoic acid analog] were studied in vitro both in the human platelet and various isolated smooth muscle preparations. SQ 27,427 was found to be a potent inhibitor of human platelet aggregation induced by arachidonic acid, ADP, epinephrine, collagen and the stable TxA2 agonists 9,11-azoPGH2 and SQ 26,655. Inhibition of platelet aggregation was achieved at concentrations of SQ 27,427 which did not alter TxB2 levels. SQ 27,427 was found to weakly inhibit the formation of TxB2 from arachidonic acid and had no effect on the synthesis of PGE2 or PGI2 from arachidonic acid. SQ 27,427 was also found to be a weak stimulator of platelet adenylate cyclase, being 1000 times less potent than PGI2. In isolated smooth muscle experiments, SQ 27,427 was shown to be a potent and specific TxA2 receptor antagonist. It caused competitive antagonism of 9,11-azoPGH2-induced contractions of vascular, respiratory and gastrointestinal smooth muscles. This antagonism was specific, as responses to norepinephrine, serotonin, PGE2, PGI2, PGF2 alpha, histamine, carbachol and KCl were not altered by SQ 27,427.
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PMID:Effects of SQ 27,427, a thromboxane A2 receptor antagonist, in the human platelet and isolated smooth muscle. 609 Jan 80

The effects of a novel compound, 1-(3-chloroanilino)-4-phenylphthalazine (MY-5445), on cyclic nucleotide metabolism and in vitro aggregation of human platelets were investigated. The concentrations of MY-5445 producing 50% inhibition of human platelet aggregation induced by 3 microM ADP, 3 micrograms/ml of collagen and 100 micrograms/ml of arachidonic acid were 0.07, 0.02 and 0.17 microM, respectively. Addition of MY-5445 significantly elevated cyclic GMP content in human platelets but had no effect on cyclic AMP content, suggesting that the drug affects principally the cyclic GMP metabolism in the platelet. Although MY-5445 had no effect on either adenylate cyclase or guanylate cyclase activity, it inhibited specifically human platelet cyclic GMP phosphodiesterase which was separated from cyclic AMP phosphodiesterase by diethylaminoethyl-cellulose column chromatography. The inhibitory effect of MY-5445 on cyclic GMP phosphodiesterase was also demonstrated by direct binding of the enzyme to MY-5445 coupled Sepharose, which was a useful tool for purifying the cyclic GMP phosphodiesterase from human platelet. These results would suggest that MY-5445 inhibits human platelet aggregation by increasing cyclic GMP content and that it provides a useful probe for elucidating the role of cyclic GMP in platelet aggregation.
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PMID:Effect of 1-(3-chloroanilino)-4-phenylphthalazine (MY-5445), a specific inhibitor of cyclic GMP phosphodiesterase, on human platelet aggregation. 614 Dec 86

The adenylate cyclase system and the number and affinities of receptors for insulin and glucagon were studied in rats treated with CCl4 and in rats that received colchicine in addition to CCl4. Liver glycogen, cAMP and total collagen content were also measured in those animals. Rats received only mineral oil or only colchicine were used as controls. In this latter group, all parameters measured were normal. Differences in liver collagen content between groups treated with CCl4 and CCl4 + colchicine were not statistically significant. Basal adenylate cyclase activity was 2-fold increased in the CCl4 group. In the animals receiving CCl4 and colchicine, adenylate cyclase activity was normal. Adenylate cyclase activity stimulated by fluoride or by glucagon was also increased in the CCl4 group. However, this increase was due to to the enhanced basal activity. The number of receptors and the affinities of the receptors of glucagon and insulin were normal in all groups. cAMP levels were found increased in the CCl4 treated animals and this was accompanied by a 90% reduction in liver glycogen. In the group treated with CCl4 + colchicine, cAMP was normal and liver glycogen was only reduced 25%. These results suggest that part of the clinical and biochemical improvements observed in the colchicine treated animals were due in part to a reversal of the alterations of the adenylate cyclase system induced by CCl4.
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PMID:Colchicine improves the alterations in the liver adenylate cyclase system of cirrhotic rats. 617 Jan 33


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