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)

Weekly injections of the catecholamine depleting agent 6-hydroxydopamine (6-OHDA) were used to denervate rabbit hearts chemically. Analyses of morphology and beta-adrenergic receptor density were made at 1, 2, and 4 weeks. Changes resulting from subacute and chronic inflammatory processes were evident by light microscopy after 1 week. At that time, electron microscopy revealed marked increases in collagen, large myocytic vacuolizations in myocytes, widened gap junctions, and myofibrillar degeneration and dropout. Receptor density was marginally increased at 2 weeks but was decreased (p less than .05) at 4 weeks (maximal [3H]dihydroalprenolol (DHA) binding in fmol/mg: 69.6 +/- 5.4 in controls vs 49.2 +/- 5.1 in 6-OHDA-treated animals). Basal, isoproterenol-stimulated and F- -stimulated adenylate cyclase activities were decreased in the 6-OHDA-treated group at 4 weeks. We conclude that administration of 6-OHDA may cause severe myocardial damage, and that this process may involve loss of some functional components of the cell membrane.
Am J Cardiovasc Pathol 1988
PMID:6-Hydroxydopamine mediated cardiotoxicity in rabbits. 314 92

We investigated properties of catecholamine-sensitive adenylate cyclase in membranes from human right atria. Basal adenylate cyclase was activated by Mg2+-ions and guanyl nucleotides [Gpp(NH)p, GTP] in a concentration-dependent manner; guanyl nucleotide activation was strongly dependent on the presence of Mg2+-ions. Catecholamines stimulated adenylate cyclase activity in the following order of potency: (-)-isoprenaline greater than (-)-adrenaline = (-)-noradrenaline greater than phenylephrine, indicating that, in human right atrium, beta 1-adrenoceptors predominate. The beta 1-agonist dobutamine and the beta 2-agonists fenoterol and procaterol activated adenylate cyclase with an intrinsic activity of 0.5-0.7 (isoprenaline = 1.0). Adenylate cyclase activation by dobutamine or procaterol was not additive with the activation induced by isoprenaline. On the contrary, combination of dobutamine (100 microM) and procaterol (10 microM) resulted in activation of adenylate cyclase which was not different from that evoked by saturating concentration of isoprenaline (10 microM), indicating that dobutamine (beta 1) and procaterol (beta 2) produce adenylate cyclase activation through stimulation of different beta-adrenoceptor subtypes. The beta 2-selective antagonist ICI 118,551 was much more potent in inhibiting procaterol-than isoprenaline-stimulated adenylate cyclase activity, whereas the beta 1-selective antagonist betaxolol inhibited isoprenaline-stimulated activity more potently. We conclude that in human right atrium, both beta 1- and beta 2-adrenoceptors are functionally coupled to the adenylate cyclase system.
J Cardiovasc Pharmacol
PMID:Human cardiac beta-adrenoceptors: both beta 1- and beta 2-adrenoceptors are functionally coupled to the adenylate cyclase in right atrium. 608 78

The purpose of this study was to identify alterations in specific enzyme and Ca2+ binding activities in cardiac sarcolemmal fractions from UM-X7.1 myopathic Syrian hamsters during the development of cardiomyopathy. Experimental and healthy control animals were examined from 25 to 200 days of age. Sarcolemmal Na+, K+-ATPase activity was depressed in the myopathic hamsters throughout the time course of this study. Sarcolemmal ATP-independent Ca2+ binding was found to be depressed in experimental animals as early as 55 days of age. Ca2+ -stimulated, Mg2+ -dependent ATPase activity was depressed in the experimental animals by 90 days of age and this decrease in enzyme activity was accompanied by a decrease in ATP-dependent Ca2+ binding capacity of the sarcolemmal membranes. Mg2+ -ATPase and Ca2+ -ATPase activities were only affected in the latter stages of the disease (155 to 200 days old). NaF, epinephrine and Gpp(NH)p stimulation of the sarcolemmal adenylate cyclase activity was also observed to be attenuated during the latter stages of the disease. These defects in adenylate cyclase system of the sarcolemmal fraction appeared specific since basal adenylate cyclase activity was not altered at any age studied. The results demonstrate that the earliest lesions in sarcolemmal activity in myopathic hamster heart occur in Na+, K+-ATPase and ATP-independent Ca2+ binding capacity. These defects correspond temporally to the initial stages of cardiac necrotic development in this strain of myopathic hamster.
Cardiovasc Res 1984 Sep
PMID:Sarcolemmal alterations during the development of genetically determined cardiomyopathy. 614 91

We examined the role of beta-adrenoceptors in regulating cardiac cell cyclic adenosine monophosphate (cyclic AMP) in concentrations during beta-receptor activation. Chick embryo cardiac cells in primary tissue culture respond to 50 microM isoprenaline with a rapid, but transient, increase in intracellular cyclic AMP. Continued exposure of these cells to this concentration of isoprenaline results in a rapid time-dependent decrease in maximum beta-receptor responsiveness. In vitro determination of adenylate cyclase and 125I-iodohydroxybenzyl pindolol specific beta-receptor binding sites in 35,000 x g particulate cell fractions and phosphodiesterase activity in cell homogenates suggest that the decrease in the cells' ability to raise intracellular cyclic AMP concentration is mainly due to an initial "uncoupling" of the beta-receptor--adenylate cyclase system. During 16 hr exposure of cells to varying isoprenaline concentrations, the magnitude of the cells' ability to increase intracellular cyclic AMP and the concentration of beta-receptor binding sites were inversely related to the isoprenaline concentration to which they had been previously exposed. On removal of isoprenaline, both beta-receptor response and receptor concentration returned slowly towards control levels over the next 24 hr. These results suggest that loss of beta-receptor responsiveness of cardiac cells during prolonged exposure to isoprenaline involves both alterations in receptor number and alterations of the adenylate cyclase system distal to the receptor.
J Cardiovasc Pharmacol
PMID:Mechanism of isoprenaline-induced refractoriness of the beta-adrenoceptor--adenylate cyclase system in chick embryo cardiac cells. 616 35

alpha-Adrenergic receptors have been grouped into two major subtypes, termed alpha 1- and alpha 2-receptors. Radioligand binding techniques have been utilized to measure the number of alpha 1- and alpha 2-receptors in a variety of tissues. [3H]Dihydroergocryptine labels the entire alpha-receptor population; the alpha-receptor subtypes may be delineated by constricting competition curves with unlabeled selective antagonists and analyzing the data with computer modeling techniques. Alternatively, alpha 1- and alpha 2-receptors may be directly identified with selective radioligands such as [3H]prazosin and [3H]yohimbine, respectively. For example, rat liver membranes have been shown to contain alpha 1- (80%) and alpha 2- (20%) receptors; the alpha 1-receptors activate glycogen phosphorylase. Radioligands have also been used to probe the mechanism by which alpha 2-receptors may inhibit adenylate cyclase activity. Agonist competition curves with [3H]dihydroergocryptine at eht human platelet's alpha 2-receptor may be resolved into two affinity components, interconvertible by guanine nucleotides. These data suggest the agonist-promoted association of the alpha 2-receptor with an additional membrane component. More direct evidence in favor of this possibility was indicated by the increase in sedimentation velocity of solubilized agonist-labeled receptor on sucrose density gradients.
J Cardiovasc Pharmacol 1982
PMID:Agonist interactions with alpha-adrenergic receptors. 617 29

Based on different affinities of various agonists and antagonists, alpha-adrenoceptors are subdivided into two subtypes, alpha 1 and alpha 2. Stimulation of alpha 1-adrenoceptors induces several changes, possibly acting as intracellular signals triggering the final cellular response. Among these changes, the increase in the cytosolic calcium ion concentration appears to be the most important signal. Increased membrane phosphatidylinositol turnover and increased cyclic guanosine 3', 5'-monophosphate (cGMP) levels under alpha 1-adrenoceptor stimulation may play a role as signals primary and secondary to the increased calcium influx, respectively. The primary intracellular signal induced by stimulation of alpha 2-adrenoceptors appears to be a fall in cellular cyclic AMP levels as a consequence of inhibition of membrane-bound adenylate cyclase. The molecular mechanisms underlying the alpha 2-adrenoceptor-mediated inhibition of this enzyme are only poorly understood, and apparently involve a guanine nucleotide-binding coupling component, which may be in part different from that involved in beta-adrenoceptor-mediated stimulation of the adenylate cyclase.
J Cardiovasc Pharmacol 1982
PMID:Signal transformation involving alpha-adrenoceptors. 617 47

The effects of prazosin on adrenergic-stimulated fat-cell lipolysis and adenylate cyclase activity were investigated. The results revealed that the antilipolytic alpha-adrenergic catecholamine effects on human fat-cell metabolism are mediated via alpha 2-receptor sites displaying extremely low affinity to prazosin, which is alpha 1-site selective. The data provide an explantation for the lack of effect of prazosin on lipid mobilization in vivo. The molecular sites mediating the lipid-lowering action of the drug, however, remain to be elucidated.
J Cardiovasc Pharmacol 1982
PMID:Effects of prazosin on human fat-cell lipolysis and adenylate cyclase activity in vitro. 617 66

Left ventricular infarctions were produced in guinea pigs, and the contractile response to beta-adrenergic and H2-histaminergic stimulation was tested in isolated perfused heart preparations. Adenylate cyclase activity and binding characteristics of sarcolemmal beta 1-, H2-, and muscarinic cholinergic receptors were determined in sarcolemmal membrane preparations of the uninvolved right ventricle of the same hearts. Three days after infarction, the positive inotropic effects of isoproterenol (2.8 X 10(-9) mol/L) and tyramine (5.5 X 10(-5) mol/L) were nearly abolished, while the inotropic effects of impromidine (4.6 X 10(-7) mol/L) and dimaprit (8.5 X 10(-6) mol/L) were not impaired. Stimulation rates of cardiac adenylate cyclase activity by isoproterenol were markedly reduced (-90%) whereas impromidine, dimaprit, and NaF revealed stimulation rates equivalent to the sham-operated control group. beta-Receptor binding studies with [3H]dihydroalprenol revealed 90% loss and nearly 10 times lowered affinity (KD) of the remaining receptors, while specific binding of [3H]tiotidine and [3H]quinuclidinyl-benzylate was unchanged in the same preparations. All of the above alterations could be prevented to a similar extent by treatment with different beta-blocking agents, but differences between the drugs were seen with respect to survival rates and reduction of infarct size. In agreement with previous findings, we conclude that the observed alterations in the nonischemic surviving myocardium are the result of specific damage of sarcolemmal beta-receptors due to excessive exposure to increased catecholamines after infarction. The stimulation of the uninvolved H2-receptors may be of therapeutic value.
J Cardiovasc Pharmacol
PMID:Effective stimulation of cardiac contractility and myocardial metabolism by impromidine and dimaprit--two new H2-agonistic compounds--in the surviving, catecholamine-insensitive myocardium after coronary occlusion. 618 27

Adenylate cyclase activity in the myocardium and aorta of Grollman one-kidney renal hypertensive rats (RHR) and sham-operated control rats was compared. The experimental rats revealed significantly higher blood pressure and cardiac hypertrophy 6-8 weeks postoperation as compared to controls. Basal, guanine nucleotide-, fluoride-, and isoproterenol-stimulated adenylate cyclase activities were consistently decreased in the myocardium of RHR as compared to control rats. Similar changes were observed in aorta of RHR; however, the magnitude of difference was greater in aorta as compared to myocardium. The kinetic properties of enzyme with regard to the Ka (quantity of agonist required for half-maximal stimulation of adenylate cyclase) values for GTP, Gpp (NH)p, and GTP-gamma-S in the absence and presence of isoproterenol and the Ka values for isoproterenol in the presence of GTP, Gpp(NH)p, or GTP-gamma-S were comparable in RHR and control rats. However, Vmax of adenylate cyclase stimulation by guanine nucleotides, isoproterenol, and fluoride was reduced in RHR as compared to control rats. No differences between RHR and control rat myocardial membranes were observed in the affinity of [3H]DHA binding. However, the number of binding sites was reduced 20-25% in RHR as compared to control rats. These data would suggest that the number of receptor--cyclase complexes may be reduced in the RHR.
J Cardiovasc Pharmacol
PMID:Properties of adenylate cyclase in the cardiovascular tissues of renal hypertensive rats. 618 37

The effects of altered thyroid state on catecholamine levels, adrenoceptor agonist potencies, and adenylate cyclase activity have been investigated using rat atria in an attempt to determine any correlation between thyroid-induced changes in these parameters. Hypothyroidism was associated with decreased growth rate, heart rate and weight, and hypertrophy of the thyroid gland; norepinephrine concentration in combined atria was also reduced. Hyperthyroid rats displayed tachycardia and marked cardiac hypertrophy, but unchanged atrial norepinephrine concentration. Measurements of inotropic potencies of phenylephrine, norepinephrine, and isoproterenol using paced left atria from hypothyroid rats indicated a possible increase in number, but not in affinity, of alpha-adrenoceptors relative to beta-adrenoceptors. The reverse was observed in hyperthyroidism. However, similar changes were not obtained when chronotropic responses to the three amines were examined using spontaneously beating right atrial preparations. Our results suggest that only in the hypothyroid state do alpha-adrenoceptors contribute significantly to the positive inotropic response to catecholamines. Adenylate cyclase activation by isoproterenol and fluoride ion was reduced in atrial membrane preparations from hypothyroid rats. Taken together, these results suggest that thyroid state modifies both pre- and post-junctional adrenergic mechanisms in rat atria.
J Cardiovasc Pharmacol
PMID:Effect of changes in thyroid state on atrial alpha- and beta-adrenoceptors, adenylate cyclase activity, and catecholamine levels in the rat. 619 Nov 38


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