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)

Cadmium (Cd) produces injurious effects on reproductive function and has been implicated in the pathogeneses of hypertension. The present article summarizes available data on alterations in the cyclic AMP system of testicular and prostatic tissue as well as in catecholamine metabolism in adrenal glands following exposure to Cd and subsequent withdrawal. Daily Cd (1 mg/kg IP) for 45 days decreased prostatic and testicular weights of mature male rats. In prostate, chronic treatment with Cd reduced cyclic AMP levels to 57% of normal values which appeared to be due to the decrease in adenylate cyclase activity since cyclic AMP metabolism by phosphodiesterase was not significantly altered. Cyclic AMP binding to prostatic protein kinase was increased following Cd administration as was the activity of the cyclic AMP-dependent form of protein kinase. In contrast to the prostate, testicular adenylate cyclase was stimulated by Cd treatment. However, the endogenous cyclic AMP levels remained unaffected since the increase in testicular adenylate cyclase was offset by a concomitant increase in the activity of phosphodiesterase. Although the activities of the cyclic AMP-dependent and the independent forms of testicular protein kinase were significantly depressed, the binding of cyclic AMP to protein kinase from testes of Cd-treated rats was not affected. Discontinuation of treatment for 28 days in rats that had previously been given the heavy metal for 45 days resulted in at least a partial reversal of several of the cadmium-induced changes in cyclic AMP metabolism of the rat prostate and testes. However, the weight of the prostate glands remained essentially in the same range as that seen in the "treated group."Data suggest that cyclic AMP metabolism in both the primary and the secondary reproductive organs is altered following chronic Cd treatment and that some changes persist even 28 days following the termination of daily exposure to the heavy metal.Cd treatment also increased adrenal weights and augmented the levels of adrenal norepinephrine and epinephrine as well as the activity of tyrosine hydroxylase. Discontinuation of the heavy metal treatment for 28 days, in rats previously injected with Cd for 45 days, restored the activity of tyrosine hydroxylase as well as the amount of norepinephrine and epinephrine. In contrast, adrenal weights were restored only partially following withdrawal of Cd treatment. Evidence indicates that the changes in adrenal catecholamine metabolism may be the result of stress induced by chronic exposure to this heavy metal. In addition, some of the untoward effects such as hyperglycemia and arterial hypertension seen during Cd toxicity might be related to increased synthesis of epinephrine in adrenal glands.
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PMID:Testicular cyclic nucleotide and adrenal catecholamine metabolism following chronic exposure to cadmium. 611 36

In an attempt to delineate the possible importance of the concentration of noradrenaline at hypothalamic noradrenergic receptor sites in a hypotensive response to a drug, the action of a new antihypertensive agent, 1-(6-morpholino-3-pyridazynyl)-2-(1-[tert-butoxycarbonyl]-2-propylidene)-diazane (GYKI 11679), on the turnover rate and the endogenous level of noradrenaline (NA) in rat hypothalamus was examined. An effective, antihypertensive i.p. dose of the compound (10 mg/kg) produced a significant but relatively short-lasting reduction in the hypothalamic noradrenaline content, whereas no change was observed in the cardiac catecholamine level. The NA turnover determinations, carried out in GYKI 11679-pretreated rats by measuring the disappearance of labeled NA at 1, 2, 3, and 5 h after the injection of the radioactive amine, showed that a 10 mg/kg i.p. dose of the compound, given 1 h prior to the i.c.v. administration of the labeled NA, increased the turnover rate of noradrenaline to a great extent. The estimated half-lives of NA in the hypothalamus of the treated and of the non-treated animals were calculated as 1.72 and 3.62 h, respectively. In vitro studies showed that the spontaneous outflow of noradrenaline from hypothalamic slices was accelerated by GYKI 11679 in a dose-dependent manner in a concentration range of 10(-5) to 10(-7) M. In a 10-fold higher range, GYKI 11679 produced inhibition of both the hypothalamic and the adrenal tyrosine hydroxylase activity but did not alter DOPA-decarboxylase, dopamine-beta-hydroxylase, or monoamine oxidase activities. Direct in vivo measurements of catecholamine synthesis by determining the 3H-catecholamines (CA) formed from [3H]tyrosine in the hypothalamus after an i.c.v. administration of the labeled precursor showed a moderate increase in [3H]CA formation following a 10 mg/kg dose of the compound. When GYKI 11679 was administered in a 75 mg/kg i.p. dose to rats, the transformation was reduced by approximately 50%. Adenylate cyclase activity measurements did not show stimulatory or inhibitory actions of the drug on the NA-stimulated adenylate cyclase of the rat hypothalamus, in accordance with previous results. This suggests that the increased NA turnover (utilization) caused by an effective, antihypertensive dose of GYKI 11679 is the direct consequence of an increased outflow, which occurs primarily in the hypothalamus. The increased activity of the noradrenergic neurons in this brain region might lead to a reduced sympathetic activity in the periphery and thus to a significant decrease in blood pressure.
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PMID:Influence on turnover and level of hypothalamic noradrenaline by a new antihypertensive agent (GYKI 11679). 611 5

The effect of i.v. sulpiride on the firing rate of dopaminergic neurons in the substantia nigra, pars compacta (SN-DA cells) and tyrosine hydroxylase (TH) activity in the caudate nucleus was studied. In rats, paralyzed with succinylcholine and artificially respirated, (-)-sulpiride (10-50 mg/kg) produced a dose-related increase in the firing rate of SN-DA cells and in TH activity. On the contrary, in rats anesthetized with halothane, (-)-sulpiride (up to 50 mg/kg) activated neither dopaminergic firing nor TH activity. However, (-)-sulpiride (10-25 mg/kg) readily reversed the inhibitory effect of i.v. apomorphine (25 micrograms/kg) on dopaminergic firing in both anesthetized and unanesthetized rats. Since sulpiride fails to inhibit DA-sensitive adenylate cyclase, it may be concluded that DA receptors, whose blockade results in increased dopaminergic firing and TH activation, are not coupled with this enzyme. Moreover, the results indicate that the mechanism responsible for firing and TH stimulation is inhibited by halothane anesthesia. The latter significantly decreased also the stimulant effect of i.v. haloperidol on striatal TH activity.
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PMID:(-)-Sulpiride activates the firing rate and tyrosine hydroxylase activity of dopaminergic neurons in unanesthetized rats. 613 78

The effects of thyrotropin-releasing hormone (TRH) and its analog gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417) on adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) levels in rat brain were investigated using a radioimmunoassay method. The time course of elevation of these nucleotides in various brain regions after administration of DN-1417 showed a peak at 5 to 15 min followed by a gradual decrease. DN-1417 (1 to 10 mg/kg i.p.) caused a dose-related increase in cyclic AMP levels in the cerebellum, cerebral cortex, striatum, nucleus accumbens, thalamus, hypothalamus and brain stem; whereas significant increases in cyclic GMP were observed in the cerebellum, nucleus accumbens and brain stem. TRH (3 to 10 mg/kg i.p.) caused significant increases of cyclic AMP in the cerebellum, cerebral cortex, nucleus accumbens, thalamus and brain stem and also caused an increase in cerebellar cyclic GMP. With one exception, DN-1417, apomorphine (Apo), methamphetamine (MAP) (all, 3 mg/kg i.p.)- and TRH (10 mg/kg i.p.)-induced increases in cyclic nucleotides were blocked by pimozide (1 mg/kg i.p., 4 hr before), a dopamine receptor blocker; the exception was a TRH-induced increase in cerebellar cyclic GMP. These increases were not blocked by propranolol (10 mg/kg i.p., 30 min before), an adrenergic beta-receptor blocker. alpha-Methyl-p-tyrosine (alpha-MT, 250 mg/kg i.p., 4 hr before), a tyrosine hydroxylase inhibitor, almost completely blocked DN-1417- and MAP-induced increases in cyclic nucleotides, slightly blocked TRH-effects, and had no effect on Apo-effects. These in vivo results were confirmed in an in vitro system using brain slices. The addition of DN-1417 (10(-4) M) or TRH (10(-3) M) significantly enhanced the spontaneous [3H]-dopamine and [3H]-norepinephrine release from the superfused slices of the rat nucleus accumbens and cerebral cortex in vitro. The addition of DN-1417 (10(-4) M) or TRH (10(-4) M) had no effect on the activities of adenylate cyclase and guanylate cyclase, although only a high concentration (10(-3) M) of DN-1417 inhibited the cyclic AMP- and cyclic GMP-hydrolytic activities in various brain region homogenates. These results suggest that DN-1417 does not produce an increase in the levels of cyclic nucleotides by direct receptor-enzyme activation, but that DN-1417 like MAP causes the increase through endogenous catecholaminergic, particularly dopaminergic activation.
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PMID:Increase in rat regional brain cyclic nucleotides by thyrotropin-releasing hormone (TRH) and its analog DN-1417. 613 95

The post-natal development of several aspects of the dopaminergic system in the rabbit have been examined. Dopamine (DA) itself was barely detectable from soon after birth up to about 7 days of age. Thereafter, dramatic increases in the retinal content of DA and also of the two major enzymes involved in its biosynthesis were observed, approaching adult values by about 16 days. These changes occur when functional synapses are being formed as judged by electrophysiological and anatomical studies. On the other hand, the post-synaptic target of these neurons, DA-stimulated adenylate cyclase could be easily detected at 3 days of age and did not appear to undergo any dramatic changes in activity during development. The affinity of haloperidol for this receptor did, however, appear to decrease with age suggesting that the receptor is 'born' in a supersensitive state but attains 'normal' properties after the onset of DA neurotransmission. Depletion of DA stores during these early stages by irreversible inhibition of biosynthesis in vivo did not appear to halt the development of tyrosine hydroxylase or have any irrevocable effects on DA neurons. This suggests that the continued presence of neurotransmitter is not necessary for the developmental process to continue that the commitment of particular neurons to become dopaminergic may be made earlier than 5-6 days post-natally.
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PMID:Ontogenesis of dopaminergic neurons in the post-natal rabbit retina: pre- and post-synaptic elements. 614 69

(R)-N6-Phenylisopropyladenosine (PIA) stimulates dopa production 3- to 5-fold in PC12 cells, with a half-maximal effective concentration (EC50) of 50 nM. This increase can be explained by a stable activation of tyrosine hydroxylase [TyrOHase; L-tyrosine, tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] when it is phosphorylated by a cAMP-dependent protein kinase. The activation of TyrOHase is mediated by the adenosine-dependent activation of adenylate cyclase (EC50 = 600 nM). PIA (10 microM) is as effective as cholera toxin or dibutyryl cAMP in activating TyrOHase in wild-type cells. Adenosine kinase-deficient mutants of PC12 were found to be resistant to PIA-dependent activation of TyrOHase (EC50 = 100-1000 nM). This phenomenon was explored in detail in one adenosine kinase-deficient mutant and was shown to occur because the mutant was resistant to the adenosine-dependent activation of adenylate cyclase. In this mutant, TyrOHase was activated 14-fold by cholera toxin, suggesting that activated TyrOHase is about 14 times as active as unactivated TyrOHase. These studies with kinase-deficient PC12 cells provide genetic evidence that adenosine-dependent activation of TyrOHase is mediated by acute increases in cAMP. When the adenosine receptor found on PC12 cells is expressed in vivo, it might function as either a presynaptic (i.e., localized on the nerve terminal) or a postsynaptic (i.e., localized on the cell body or dendrite) receptor that regulates rates of transmitter synthesis in response to cell activity.
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PMID:Adenosine-dependent activation of tyrosine hydroxylase is defective in adenosine kinase-deficient PC12 cells. 614 82

The role of the presynaptic alpha and beta-adrenoceptors on the regulation of tyrosine hydroxylase activity was studied in guinea pig atria depolarized with 50 mM K+. The presence of the beta-blocker propranolol (0.1 microM), alpha-blockers phentolamine (0.31 microM) or yohimbine (0.3 microM) or the alpha-agonist clonidine (0.1 microM) in the incubation medium did not affect tyrosine hydroxylase activation by 50 mM K+. On the contrary, the beta-agonist isoproterenol (0.012 microM) potentiated the activation produced by 50 mM K+, effect blocked by propranolol. Also the phosphodiesterase inhibitor, 1-methyl-3-isobutyl-xanthine (100 microM), facilitated tyrosine hydroxylase activation by potassium. Isoproterenol might exert its facilitatory effect through the stimulation of presynaptic beta-adrenoceptors, activation of adenyl cyclase and consequent increase of the intraneuronal concentration of cAMP. Noradrenaline synthesis in guinea pig atria depolarized by K+ seems to be unrelated to the stimulation of presynaptic adrenoceptors and also independent of the regulation of neurotransmitter release.
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PMID:Presynaptic adrenoceptors on the regulation of tyrosine hydroxylase activation by potassium. 615 72

Forskolin stimulates the conversion of tyrosine to dopamine in slices and synaptosomes from rat striatum, in synaptosomes from rat hypothalamus, and in slices from bovine retina. In striatal synaptosomes, there is an approximately 80% stimulation of dopamine formation from tyrosine, but no effect with DOPA as substrate, suggesting that the effect is on tyrosine hydroxylase. Stimulation is saturable with a half-maximal effect at under 1 microM forskolin. Forskolin stimulation is additive with, and hence independent of , activation due to KCl, but not that due to dibutyryl-cyclic AMP. Stimulation of dopamine synthesis by forskolin may provide an approach for elucidating the regulation of the adenylate cyclase system associated with catecholaminergic nerve endings.
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PMID:Forskolin stimulates the conversion of tyrosine to dopamine in catecholaminergic neural tissue. 630 97

In the essay we have described what we consider to be criteria for the selection of a simple mammalian model system for studying synaptic mechanisms and have shown how the dopamine-containing amacrine neuronal system of the rat retina fit these criteria. Thus, the retina contains a defined population of neurons which secrete dopamine. The neuronal activity of the dopamine-containing cells can be reproducibly controlled by the experimenter using a physiological stimulus, light. The neurons are activated by exposure to light and are relatively quiescient in the dark. We have described how this model system has been employed to study the regulation of dopamine synthesis in response to both short term and long term changes in neuronal activity. Short term exposure to light increases dopamine turnover and activates tyrosine hydroxylase, which is characterized by a decrease in the Km of the enzyme for the pteridine cofactor. After long term exposure to light the Km for the cofactor returns to the value found for animals in the dark, while the Vmax of the enzyme increases. The change of Vmax is the consequence of an increase in the specific activity of the enzyme. Evidence has also been presented illustrating the usefulness of the dopamine neuronal system of retina for studying postsynaptic mechanisms. Retina appears to contain only D-1 receptors, which are linked to adenylate cyclase. Since dopamine release in the retina can be experimentally manipulated by light, it may be possible to study the consequence of prolonged activation of receptors by dopamine on postsynaptic biochemistry.
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PMID:Dopamine neurons of the retina: a simple method system for studying synaptic regulatory mechanisms. 701 14

The effect of the alpha adrenoceptor blocking agent yohimbine on cerebral dopamine metabolism has been investigated in the rat. Yohimbine (1 to 10 mg/kg i.p.) increased in both striatum and limbic areas 1) homovanillic acid and dihydroxyphenylacetic acid levels, 2) tyrosine hydroxylase activity measured in vitro, 3) the in vivo accumulation of dihydroxyphenylalanine after NSD 1015 and 4) the rate of dopamine disappearance after alpha-methyl-p-tyrosine. The inability of clonidine to prevent the yohimbine-induced enhancement of striatal homovanillic acid levels in doses that antagonize the yohimbine-induced increase in noradrenaline turnover as well as the failure of other alpha adrenoceptor blocking agents (tolazoline, phentolamine and prazosin) to increase dopamine metabolism suggest that alpha adrenoceptors are not involved in the yohimbine-induced alteration of dopamine metabolism. Similarly to neuroleptic agents, yohimbine reduced striatal acetylcholine concentrations and counteracted the dopamine (10(-5) M)-induced inhibition of the potassium-evoked release of [3H]acetylcholine from slices of caudate nucleus. Yohimbine failed to further enhance striatal homovanillic acid levels in animals pretreated with a supramaximal dose of haloperidol. Moreover, in rats treated with haloperidol for 10 days, the effect of yohimbine on striatal homovanillic acid and acetylcholine levels was markedly reduced. It is concluded that yohimbine possesses postsynaptic dopamine receptor blocking properties in addition to its ability to inhibit alpha adrenergic receptors. The failure of yohimbine to affect dopamine-sensitive adenylate cyclase activity in striatal homogenates suggests an action of the compound on the D2 receptor.
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PMID:Antidopaminergic properties of yohimbine. 719 14


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