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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The calcium ion concentration measured in rat kidney mitochondria, isolated from vasopressin treated tissue, has a dose response characteristic in which the calcium concentration reached a minimum at low doses of vasopressin (2 mU/ml), at higher doses of hormone the mitochondrial calcium ion concentration increases reaching a value close to that of the controls with vasopressin (100 mU/ml). This efflux and subsequent uptake of mitochondrial calcium has been shown to be a direct effect of the varying cyclic AMP concentrations. Sodium and water permeability effects of vasopressin have been shown in toad bladder to have different dose response characteristics. Maximum sodium transport occurs at a lower dose of vasopressin (2 mU/ml) and is believed to be associated with direct permeability effects of the hormone. Maximum water transport occurs at a higher dose of vasopressin (100 mU/ml) over a concentration range associated with hormone-stimulated adenylate cyclase activity. The water transport response to low doses of vasopressin may be potentiated by aldosterone treatment, an effect that can be related to the inhibition of tissue phosphodiesterase activity and subsequent increased cyclic AMP concentrations. In steroid depleted conditions the cyclic AMP medicate efflux of mitochondrial calcium ions, that occurs at low doses of vasopressin, may prevent the release of membrane bound calcium ions and thus inhibit the water permeability effect of the hormone. Higher levels of cyclic AMP reverse this inhibitory effect and give rise to an increased water flow. It is concluded that cyclic AMP and intracellular concentrations of calcium ion act as inter-related mediators of antidiuretic hormone action.
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PMID:Role of mitochondrial Ca2+ in antidiuretic hormone action. 18 79

The in vitro effects of theophylline and aminogluthetimide upon basal and ACTH stimulated cAMP, cortisol and aldosterone responses of normal human adrenocortical tissue were evaluated. Theophylline increased basal cAMP levels and cortisol output, however, basal aldosterone output was depressed. Theophylline in concert with ACTH depressed cortisol and aldosterone output. Aminogluthetimide alone did not affect basal cAMP levels, however, the normal cAMP response to ACTH was delayed in aminogluthetimide pre-treated adrenals. Aminogluthetimide also depressed basal and ACTH stimulated cortisol and aldosterone output with the latter being more sensitive. The findings indicate that both theophylline and aminogluthetimide produce effects upon the adrenal in addition to inhibition of phosphodiesterase and cholesterol side-chain cleavage, respectively. Further, theophylline depression of ACTH stimulated steroid output may be helpful in understanding the interplay between a number of factors in the control of adrenal steroid biosynthesis and release.
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PMID:In vitro effects of theophylline and aminogluthetimide upon basal and ACTH induced cAMP levels and steroid output by the normal human adrenal gland. 20 41

Effects of angiotensin II on corticoid biogenesis and cAMP levels in the zona fasciculata-reticularis (the decapsulated fraction) and the zona glomerulosa (the capsular fraction) from the rat adrenal gland have been studied. Angiotensin II exclusively stimulated steroidogenesis in the zona glomerulosa without stimulation of the cAMP system, suggesting that steroidogenic action of this polypeptide does not involve the adenylate cyclase system. Angiotensin II was also found to stimulate cAMP-phosphodiesterase activity in the zona glomerulosa. An elevation of calcium concentration in the incubation medium has been observed to be effective in stimulating the production of aldosterone and cAMP by the capsular fraction. Angiotensin II caused a significant enhancement of the steroidogenic response of the capsular fraction to increasing calcium concentration regardless of the response of the cAMP system to calcium. This steroidogenic effect of angiotensin II was completely abolished by calcium antagonists added to the incubation medium without any inhibitory effect on the calcium-induced accumulation of tissue cAMP. These results suggest that angiotensin II acts on the adrenal II acts on the adrenal glomerulosa cell to increase intracellular calcium, which in turn directly stimulates steroidogenesis concomitant with the increased activity of phosphodiesterase.
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PMID:Studies on cyclic nucleotides in the adrenal gland. VIII. Effects of angiotensin on adenosine 3',5'-monophosphate and steroidogenesis in the adrenal cortex. 21 76

The responses of the cyclic AMP-generation system and corticosteroids biosynthesis to ACTH and angiotensin II and cholesterol and other lipid contents in adrenal tissues were estimated in the in vitro experiments in 3 cases of Cushing's syndrome due to ACTH-responsive and unresponsive adenomas, one case of Cushing's disease (diffuse hyperplasia), one case of primary aldosteronism and one normal subject. The responses of cAMP accumulation and corticosteroids production to ACTH in in vitro studies were quite in good agreement with the in vivo responses of plasma cortisol by ACTH infusion test. The adenylate cyclase activity decreased and the phosphodiesterase activity increased in the case of hyperplasia and in one case of ACTH-responsive adenoma, whereas the basal cyclic AMP content was slightly more in ACTH-responsive adenoma and maximal in hyperplasia compared with that of the normal adrenal tissue. The characteristic features observed in ACTH-unresponsive adenoma were the largest amount of the basal corticosteroids production and esterified cholesterol content, and the lowest content cAMP. These results indicate that there was not always the consistent correlation between the cAMP-generation system, corticosteroids and aldosterone production, and conversion of cholesterol to pregnenolone by the stimulation of ACTH and angiotensin II in adrenal tumors.
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PMID:Comparative study of cyclic AMP-generation system, steroid biosynthesis and lipid metabolism in vitro in ACTH responsive and unresponsive adrenal tumors. 22 40

The role of cyclic AMP in the regulation of aldosterone production by adrenocorticotropic hormone (ACTH), angiotensin II (A II), potassium, and serotonin was examined in collagenase-dispersed adrenal glomerulosa cells. The ability of 8-bromo cyclic AMP and choleragen to stimulate maximum aldosterone production indicated that cyclic AMP could act as second messenger for certain of the aldosterone-stimulating factors. The actions of ACTH and choleragen on aldosterone and cyclic AMP production were correlated in dog and rat cells, and a similar relation was seen during stimulation of rat cells by serotonin. In contrast, A II and potassium did not cause changes in cyclic AMP formation while stimulating aldosterone production. Intracellular and receptor-bound cyclic AMP were increased 3-fold by 10(-7) M ACTH but not by A II. Addition of a phosphodiesterase inhibitor increased the magnitude of the cyclic AMP response to ACTH but did not change the lack of stimulation by A II or potassium. In dog cells, the effects of A II and potassium on aldosterone production were partially additive to those of ACTH, choleragen, and 8-bromo cyclic AMP. In contrast, no additivity was observed between A II and potassium, or between combinations of the cyclic AMP-dependent stimuli. These results indicate that the actions of ACTH on aldosterone secretion are mediated by cyclic AMP formation, whereas A II and potassium stimulate aldosterone production through an independent mechanism. The lack of additivity between steroid responses to A II and potassium suggests that these factors could share a common mode of action on steroidogenesis in zona glomerulosa cells.
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PMID:The role of cyclic AMP in aldosterone production by isolated zona glomerulosa cells. 22 59

Atrial stretch causes the release of atriopeptin (AP, ANF) from preformed vesicular storage sites. The circulating hormone acts on unique receptor sites (containing guanylate cyclase) to release guanosine 3',5'-cyclic monophosphate (cGMP) that mediates the natriuresis and vasodilation and probably the suppression of renin, aldosterone, and vasopressin. The biological effects of atriopeptin are transient because of the rapid inactivation of the circulating hormone (by neutral endopeptidase or clearance receptors) or the second messenger (by cGMP-phosphodiesterase). Heart failure due to chronic cardiac volume overload [aortovenocaval (A-V) fistula] exhibits markedly elevated circulating AP blood levels and urinary cGMP levels, accompanied by induction of ventricular AP gene and protein expression and release. Pharmacological manipulation of endogenous AP, either by inhibiting cGMP phosphodiesterase (i.e., mediator prolongation) or neutral endopeptidase (i.e., prolongation of hormone half-life) in A-V fistula animals results in profound natriuresis and diuresis without hypotension. These pharmacological maneuvers bypass the suppressed renal response to exogenous AP seen in heart failure and provide a rational therapeutic strategy based on our understanding of the underlying physiological and pathological mechanisms.
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PMID:Effect of pharmacological manipulation of endogenous atriopeptin activity on renal function. 131 20

In contrast to the bipyridine derivatives amrinone and milrinone, the phosphodiesterase III/IV inhibitor enoximone is an imidazolone that creates the possibility of inhibiting adrenal steroid synthesis, as has already been demonstrated for other imidazoles, e.g. ketoconazole and etomidate. To clarify this point we carried out a double-blind sequential study in seven healthy volunteers. METHODS. After obtaining the approval of the ethics committee and the written consent of the volunteers, 1.25 mg/kg enoximone or saline was infused intravenously over a period of 20 min using a randomized crossover design with an interval of at least 5 days between the two trials. Twenty minutes after administration of the drug, 250 micrograms ACTH was injected. Plasma cortisol was measured prior to stimulation of the adrenal cortex and 30, 60 and 120 min afterwards; levels of aldosterone and 11-desoxy-cortisol were determined after 60 min. Standard radioimmunoassays were used. Haemodynamic parameters were measured non-invasively. RESULTS. In contrast to the placebo, enoximone resulted in a significant (P < 0.01) increase in the cardiac index (from 3.2 +/- 0.7 to 3.9 +/- 0.9 l min-1 m-2) and heart rate (from 69 +/- 11 to 81 +/- 8 min-1) and a decrease in peripheral resistance (from 1120 +/- 202 to 894 +/- 183 dyn s cm-5); blood pressure fell only slightly. Following injection of ACTH there were significant increases in cortisol (from 63 +/- 29 to 274 +/- 58 micrograms/l), aldosterone (from 86 +/- 37 to 300 +/- 105 ng/l) (both P < 0.001) and 11-desoxycortisol (from 5.3 +/- 1.2 to 9.8 +/- 4.6 micrograms/l; P < 0.05). There was no difference between enoximone and placebo at any time (P > 0.2). CONCLUSIONS. This study confirms the inodilation caused by enoximone. The normal response to ACTH rules out a direct inhibitory effect of a loading dose of 1.25 mg enoximone on the adrenal cortex. As the concentration of the major metabolite of enoximone, the sulphoxide, has been shown to surmount that of the parent drug after 40 min, this also holds true for the metabolite. We conclude that in contrast to etomidate, which causes a substantial reversible adrenal suppression after a single dose of 0.2 mg/kg, enoximone 1.25 mg/kg did not interfere with corticosteroid synthesis or release. Taking into account the metabolism and pharmacokinetics of this inodilator, there is no reason to expect an inhibitory effect even after repeated dosage.
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PMID:[Suppression of the adrenal cortex by enoximone. A proband study with documentation of the hemodynamic course]. 146 55

An adrenal cGMP-stimulated phosphodiesterase (cGS-PDE) has been shown to mediate atrial natriuretic peptide (ANP)-induced reductions in aldosterone secretion and cAMP levels in primary bovine glomerulosa cells. High concentrations of cGS-PDE have been localized to the zona glomerulosa cell layer of the adrenal cortex using biochemical and immunological techniques. Immunoblot analysis using an affinity-purified, isozyme-specific antiserum revealed a single band that comigrated with a purified cGS-PDE (105 kDa) (1) and that was most highly concentrated in the outermost 1-2 mm of the cortex, representing the capsule and zona glomerulosa regions. Greater than 90% of the overall phosphodiesterase activity present in tissue extracts prepared from these regions was immunoprecipitated using a solid-phase monoclonal antibody reagent, indicating the cGS-PDE as the predominant phosphodiesterase isozyme. Immunohistochemical staining experiments of frozen thin sections of intact adrenal tissue revealed that the cGS-PDE present in this region was localized in the glomerulosa cells themselves. The role of this isozyme as a mediator of ANP-induced decreases in intracellular cAMP concentrations and aldosterone production was tested in primary cultures of bovine adrenal glomerulosa cells. In cells stimulated by ACTH, ANP treatment produced dose-dependent reductions in aldosterone secretion and cellular cAMP content over the same concentration range. Increases in aldosterone production elicited by three cell-permeable cAMP derivatives (8-bromo-cAMP, 8-p-chlorophenylthio-cAMP, and N6-2'-O-dibutyryl-cAMP) were antagonized by ANP, indicating a site of action distal to adenylate cyclase for this hormone. Because the relative magnitude of the ANP effect differed depending upon the derivative used, the three derivatives were compared with respect to their relative rates of in vitro hydrolysis by adrenal cGS-PDE. A positive correlation between their rates of hydrolysis and the degree to which the steroidogenic response produced by these derivatives was antagonized by ANP was demonstrated, further suggesting an ANP-induced activation of the cGS-PDE as being responsible for this effect. The possible contribution of an additional pathway mediated by an inhibitory guanine nucleotide binding regulatory protein (Gi) acting on adenylate cyclase was tested by pretreatment of primary glomerulosa cells with pertussis toxin. Levels of pertussis toxin sufficient to inhibit subsequent in vitro ribosylation did not significantly alter the ANP effect on aldosterone production, although a partial reduction in the ANP effect on cAMP levels was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:High concentrations of a cGMP-stimulated phosphodiesterase mediate ANP-induced decreases in cAMP and steroidogenesis in adrenal glomerulosa cells. 184 62

Adrenal glomerulosa was examined for the presence of an adrenergic influence on aldosterone production. Cultured rat adrenal capsular explants were transferred to a perifusion system where the effect of exposure to catecholamines on aldosterone production was assessed. At 10(-6) M, isoproterenol greater than epinephrine greater than norepinephrine significantly stimulated aldosterone production, whereas at 10(-8) M only isoproterenol showed significant stimulation. Propranolol, a beta-adrenoreceptor antagonist, inhibited stimulation by epinephrine, and the phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine, enhanced stimulation by a submaximal dose of epinephrine. Epinephrine and norepinephrine were found by radioenzymatic assay to be present in fresh as well as cultured capsular tissue, although levels were considerably lower in tissue that had been in culture (about one tenth that of fresh tissue). The epinephrine-norepinephrine ratio was similar in capsule and medulla, suggesting a medullary source of capsular catecholamines. Whether catecholamines in the capsule arose from the in vitro manipulation of adrenal tissue or existed in vivo is unclear. In summary, beta-agonists stimulate aldosterone production in cultured rat capsular explants.
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PMID:Beta-adrenergic stimulation of aldosterone production by rat adrenal capsular explants. 241 Feb 37

The rationale of combining vasodilatation with positive inotropic intervention in the treatment of chronic heart failure has found a new implementation in the "inodilator" drugs. Inodilators are characterized by the properties of exerting positive inotropic effect and inducing systemic vasodilatation. The cellular mechanisms involved in the regulation of contractility of cardiac and vascular muscle and the pathophysiological events occurring in heart failure are briefly discussed, and the pharmacological profile as well as the therapeutic use of these drugs are reviewed. On the basis of the mechanism of action, two groups of inodilators are distinguished, the phosphodiesterase inhibitors and the dopaminergic agents. The increase of [cAMP]i induced by the phosphodiesterase inhibitors is responsible for their vasodilating effect and for the positive inotropic action, but many of them have in addition the ability to enhance the Ca2+ sensitivity of cardiac contractile proteins. The complex organization and the cardinal role of the catecholaminergic receptor system in the control of cardiovascular function and its contribution to the pathophysiological events occurring in heart failure are the rational basis of the therapeutic use of dopaminergic agents. These drugs, acting on DA, beta-, and alpha-receptors, exert not only positive inotropic and vasodilating effects, but also a diuretic action, and can reduce aldosterone and renin secretion, blunt an excessive sympathetic activity, and possibly promote the release of atrial natriuretic peptide. The multireceptor mechanism of dopamine-like drugs, which accounts for their favorable hemodynamic, neurohumoral, and diuretic effects, represents the most promising approach to inodilator therapy.
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PMID:Present and future trends in research and clinical applications of inodilators. 248 38


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