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)

Atrial natriuretic peptides (ANP) stimulate renal Na+ excretion by poorly understood mechanisms, possibly involving direct inhibition of Na+ transport in the renal medulla. We have previously shown that human ANP 4-28 (hANP) inhibits Na+ entry-dependent O2 consumption (QO2) in rabbit inner medullary collecting duct (IMCD) cells. Because ANP actions in other tissues appear to be mediated by guanosine 3',5'-cyclic monophosphate (cGMP), the present studies examined the role of cyclic nucleotides in IMCD cell responses to ANP. 8-Bromo-cGMP (8-BrcGMP) diminished QO2 by 23.5 +/- 1.2% (SE) in IMCD cells but had no effect in cells derived from outer medullary collecting duct (OMCD); dibutyryl-adenosine 3',5'-cyclic monophosphate (cAMP) was without effect in IMCD cells. The inhibitory effect of BrcGMP was not additive with ANP, amiloride, or ouabain. Amphotericin, which enhances Na+ entry into cells, prevented the inhibitory effect of 8-BrcGMP. These results indicate that 8-BrcGMP, like ANP, inhibited Na+ entry in IMCD cells. hANP stimulated a 10-fold increase in cGMP in IMCD cells without altering IMCD cAMP levels or OMCD cGMP levels. Isobutyl methylxanthine, which inhibits phosphodiesterase activity, enhanced both cGMP accumulation and inhibition of QO2 by submaximal levels (10(-9) M) of ANP. Nitroprusside raised cGMP levels in both IMCD and OMCD cells but inhibited QO2 only in IMCD cells. We conclude that cGMP mediates the transport effects of ANP in IMCD cells. Our results indicate that cGMP may play an important role in the regulation of sodium transport in renal epithelia.
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PMID:cGMP mediates effects of atrial peptides on medullary collecting duct cells. 243 76

Cardiotonic agents influence myocardial energy consumption by vasodilation, which may reduce energy demand, and by inotropism, which may increase it. To distinguish between the two effects, myocardial oxygen consumption must be analyzed in relation to its hemodynamic determinants. The coupling of myocardial oxygen consumption with its determinants was investigated in 22 patients with idiopathic dilated cardiomyopathy (NYHA Class II and III). Predicted myocardial oxygen consumption by the pressure-work index, the Bretschneider index, and the pressure-volume area correlated moderately with measured myocardial oxygen consumption (r = 0.57, p less than 0.001; r = 0.52, p less than 0.005; and r = 0.63, p less than 0.001). Multiple regression analysis, including left ventricular peak systolic wall stress, systolic stress-time integral, pressure-volume work, maximum rate of left ventricular pressure rise, and mean velocity of circumferential fiber shortening indicated that systolic stress-time integral is the major determinant of myocardial oxygen consumption (r = 0.75, p less than 0.001) in these patients. Enoximone, a phosphodiesterase inhibitor, has an inotropic and a vasodilating effect. To investigate the inotropic portion of the energy cost of this phosphodiesterase inhibitor, the influence of enoximone on myocardial oxygen consumption and systolic stress-time integral was compared with the effects of nitroprusside, which is a vasodilator only. Nitroprusside (10 patients) and enoximone (12 patients) reduced left ventricular systolic stress-time integral from 109 +/- 22 to 71 +/- 21 (p less than 0.005) and from 104 +/- 23 to 42 +/- 10 (p less than 0.001) 10(3) dynes.sec/cm2, respectively. Myocardial oxygen consumption decreased from 159 +/- 44 to 112 +/- 23 (p less than 0.005) and from 134 +/- 28 to 109 +/- 21 (p less than 0.001) microliters/beat/100 g, respectively. In both groups, there was a significant correlation between the decrease in myocardial oxygen consumption and the decrease in systolic stress-time integral. The slopes of the respective linear regression lines were significantly different (1.27 for nitroprusside and 0.51 nl.cm2/100 g.dynes.sec for enoximone, p less than 0.05), indicating a smaller decrease of myocardial oxygen consumption for a given decrease of stress-time integral with enoximone. Applying the pressure-work index or the pressure-volume area instead of systolic stress-time integral yielded comparable results. Thus, vasodilation reduces myocardial oxygen consumption in proportion to the reduction of stress-time integral. With enoximone, the energy-saving effect of vasodilation is counteracted in part by the increased energy d
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PMID:Myocardial energetics in patients with dilated cardiomyopathy. Influence of nitroprusside and enoximone. 252 32

cGMP is a second messenger that mediates numerous metabolic events; in the present work a role in myeloid cell differentiation was demonstrated. Nitroprusside and NaNO2, which activate cytosolic guanylate cyclase and increase the intracellular cGMP concentration, induced granulocytic differentiation of the human promyelocytic cell line HL-60; differentiation was measured by acquisition of the OKM1 antigen, morphological changes, and nitroblue tetrazolium reduction. When theophylline, a phosphodiesterase inhibitor, which by itself induced modest differentiation, was added to nitroprusside or NaNO2, differentiation increased in an additive fashion. The degree of differentiation correlated with the increase in the intracellular cGMP concentration. 8-Bromoguanosine 3',5'-cyclic monophosphate, a membrane-permeable cGMP analogue, also induced differentiation of HL-60 cells but was much more effective in the presence of theophylline, with the two agents interacting synergistically. The effect of theophylline in these studies could not be attributed to increasing the intracellular cAMP concentration. Dimethyl sulfoxide, and established inducer of differentiation of HL-60 cells, markedly enhanced the differentiation induced by nitroprusside and NaNO2.
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PMID:cGMP-induced differentiation of the promyelocytic cell line HL-60. 255 Sep 30

Synthetic rat atrial natriuretic peptide (ANP) was examined for effects on guanylate-and on adenylate cyclase activity in ciliary process homogenates and for effects on intraocular pressure in the albino rabbit eye. Ciliary process guanylate cyclase was associated predominantly with the particulate fraction and was partially activated by ANP (EC50, approximately 1 nM) relative to a maximal dose of Na Nitroprusside (2 uM), whereas particulate adenylate cyclase (basal as well as forskolin-stimulated activity) showed no responses to ANP at doses up to 0.3 uM. Particulate cAMP phosphodiesterase activity was stimulated by low doses of cGMP (1-5 uM) in ciliary processes. Thus, ANP, acting via guanylate cyclase, has the potential to regulate phosphodiesterase activity and indirectly decrease cAMP levels in membranes derived from ciliary processes. Intravitreous injection of ANP (2-4 ug/eye) caused a small decrease (1-1.5 mm Hg) in intraocular pressure measured 16-24 hours after injection but the pressure had returned to normal by 40 hours. The findings demonstrate regulation of biochemical and pharmacological responses by ANP in the albino rabbit eye suggesting that this peptide may play a physiological role in secretory functions of ciliary processes.
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PMID:Atrial natriuretic peptide (ANP), guanylate cyclase, and intraocular pressure in the rabbit eye. 289 Apr 98

To assess whether the phosphodiesterase inhibitor enoximone has a specific, direct effect on left ventricular diastolic function distinct from its inotropic and vasodilator actions, we compared the effects of enoximone and the pure vasodilator nitroprusside in 11 patients with severe heart failure. Mean (+/- SEM) left ventricular ejection fraction was 0.20 +/- 0.03. Simultaneous left ventricular pressure and radionuclide angiographic volume were obtained at baseline, during infusion of nitroprusside, and after intravenous administration of enoximone. Left ventricular end-diastolic pressure (LVEDP) and volume (LVEDV) decreased with both agents (p less than .01 vs control); LVEDP was lower for nitroprusside than for enoximone (p less than .01) despite a similar LVEDV. Nitroprusside decreased the time constant of exponential left ventricular pressure decay, TL (measured by the logarithmic method), from 84 +/- 10 to 65 +/- 8 msec (p less than .01) but had no significant effect on TD (measured by the derivative method), maximum negative dP/dt, or the peak rate of early diastolic filling. Enoximone shortened TL from 86 +/- 12 to 61 +/- 9 msec (p less than .01) and increased maximum negative dP/dt from 897 +/- 101 to 1135 +/- 134 mm Hg/sec (p less than .01) but did not affect TD or the peak filling rate. The left ventricular diastolic pressure-volume relation was shifted downward in only three of 11 patients on nitroprusside and three of 11 patients on enoximone, and these shifts were attenuated by adjusting for simultaneous changes in right atrial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Diastolic function in patients with severe heart failure: comparison of the effects of enoximone and nitroprusside. 295 73

In mouse parotid acini both cholinergic and beta-adrenergic agonists increased intracellular levels of cyclic-GMP (c-GMP) as well as amylase release. The derivative of c-GMP, 8-bromo-c-GMP, mimicked the effects of cholinergic and beta-adrenergic stimulation on amylase release. Nitroprusside (NP), hydroxylamine (HA) and sodium azide (NaA) increased c-GMP levels and also enhanced amylase release in a dose-dependent manner; cyclic-AMP (c-AMP) levels were not affected. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (MIX) enhanced the effects of carbachol on both c-GMP accumulation and amylase release. These results suggest that c-GMP may mediate the actions of cholinergic agonists and at least partially mediate the actions of beta-adrenergic agonists on mouse parotid enzyme release.
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PMID:Does cyclic GMP mediate amylase release from mouse parotid acini? 618 89

The role of cGMP as a second messenger for renin secretion is contentious. This was investigated using a superfused collagenase-dispersed rat kidney cortex cell preparation devoid of indirect influences on renin secretion. Nitroprusside, atriopeptin II and 8-Br-cGMP all increased renin release but the dose-response relationships were biphasic. At low dose ranges there was a positive correlation between increasing drug concentration and renin secretion, but at high drug concentrations, a negative correlation was apparent. Methylene blue, a guanylate cyclase inhibitor, also suppressed baseline renin release at 10(-5) and 10(-6) M, but stimulated release at 10(-3) M. Using mid-range drug concentrations, the cGMP specific phosphodiesterase inhibitor MB22948 potentiated renin release in response to nitroprusside and 8-Br-cGMP. Inhibition of guanylate cyclase with either methylene blue or LY83583 attenuated renin release in response to nitroprusside, but, as expected, had no effect on 8-Br-cGMP induced release. We conclude that, under physiological conditions, cGMP is a stimulatory second messenger for renin release. This activity is mimicked at low dose ranges by 8-Br-cGMP, nitroprusside and atriopeptin II. In response to high doses of these drugs an unknown inhibitory pathway is activated and this opposes, in a dose-related manner, the stimulatory actions of cGMP for renin release.
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PMID:Cyclic GMP-linked pathway for renin secretion. 770 14

cGMP enhances cAMP accumulation in platelets via cGMP-inhibited phosphodiesterase (PDE3) [Maurice and Haslam (1990) Mol. Pharmacol. 37, 671-681]. However, cGMP might also limit cAMP accumulation by activating cGMP-stimulated phosphodiesterase (PDE2). We therefore evaluated the role of PDE2 in human platelets by using erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) to inhibit this enzyme selectively. IC50 values for the inhibition of platelet PDE2 by EHNA, with 10 microM cAMP as substrate in the absence and in the presence of 1 microM cGMP, were 15 and 3 microM respectively. Changes in platelet cyclic [3H]nucleotides were measured after prelabelling with [3H]adenine and [3H]guanine. Nitroprusside (NP) caused concentration-dependent increases in [3H]cGMP and a biphasic increase in [3H]cAMP, which was maximal at 10 microM (49+/-6%) and smaller at 100 microM (32+/-6%) (means+/-S.E.). In the presence of EHNA (20 microM), which had no effects alone, NP caused much larger increases in platelet [3H]cAMP (125+/-14% at 100 microM). EHNA also enhanced [3H]cGMP accumulation at high NP concentrations. In accord with these results, EHNA markedly potentiated the inhibition of thrombin-induced platelet aggregation by NP. The roles of cAMP and cGMP in this effect were investigated by using 2', 5'-dideoxyadenosine to inhibit adenylate cyclase. This compound decreased the accumulation of [3H]cAMP but not that of [3H]cGMP, and diminished the inhibition of platelet aggregation by NP with EHNA. We conclude that much of the effect of NP with EHNA is mediated by cAMP. Lixazinone (1 microM), a selective inhibitor of PDE3, increased platelet [3H]cAMP by 177+/-15%. This increase in [3H]cAMP was markedly inhibited by NP; EHNA blocked this effect of NP. Parallel studies showed that NP suppressed the inhibition of platelet aggregation by lixazinone. EHNA enhanced the large increases in [3H]cAMP seen with 20 nM prostacyclin (PGI2), but had no effect with 1 nM PGI2. NP and 1 nM PGI2 acted synergistically to increase [3H]cAMP, an effect attributable to the inhibition of PDE3 by cGMP; EHNA greatly potentiated this synergism. In contrast, NP decreased the [3H]cAMP accumulation seen with 20 nM PGI2, an effect that was blocked by EHNA. The results show that, provided that cGMP is present, PDE2 plays a major role in the hydrolysis of low cAMP concentrations and restricts any increases in cAMP concentration and decreases in platelet aggregation caused by the inhibition of PDE3. At high cAMP, PDE2 plays the major role in cAMP breakdown, whether cGMP is present or not.
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PMID:Activation of cGMP-stimulated phosphodiesterase by nitroprusside limits cAMP accumulation in human platelets: effects on platelet aggregation. 916 26

The acute hemodynamic effects of the phosphodiesterase (PDE) III inhibitor saterinone were compared with dobutamine and sodium nitroprusside in 12 patients with idiopathic congestive cardiomyopathy (NYHA III). Hemodynamic measurements were obtained with a Swan-Ganz thermodilution catheter. At the peak of its dose-response curve, saterinone induced an increase in cardiac index (+102%), stroke volume (+97%), and heart rate (+6%), paralleled by a decrease in pulmonary capillary wedge pressure (-46%), right atrial pressure (-51%), pulmonary arterial pressure (systolic -32%, diastolic -45%, mean -38%), systemic blood pressure (systolic -3%, diastolic -13%, mean -9%), systemic vascular resistance (-54%), and pulmonary vascular resistance (-58%). Dobutamine had similar effects on cardiac index (+106%) and stroke volume (+87%) but lacked vasodilatory characteristics. In contrast to dobutamine, both nitroprusside and saterinone demonstrated more pronounced vasodilatory effects. Nitroprusside was less effective on cardiac index (+66%) and stroke volume (+56%) than was saterinone. The double product was markedly increased by dobutamine (+28%), did not change with saterinone treatment (+2%), and decreased with nitroprusside (-10%). This indicates that according to double product, only the application of dobutamine caused a relevant increase in myocardial oxygen consumption. Saterinone was demonstrated to be a safe and potent drug on short-term application; it combines the vasodilating properties of sodium nitroprusside with the positive inotropic effects of dobutamine without major changes in myocardial oxygen consumption.
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PMID:Saterinone, dobutamine, and sodium nitroprusside: comparison of cardiovascular profiles in patients with congestive heart failure. 978 32

Prostaglandin-induced cAMP elevation restrains key signaling pathways in platelet activation including Ca(2+) mobilization and integrin alphaIIbbeta3 affinity regulation. We investigated how cAMP turnover by cyclic nucleotide phosphodiesterases (PDEs) regulates platelet activation. In washed human platelets, inhibition of all PDEs and also specific inhibition of PDE3 but not of PDE5 suppressed thrombin-induced Ca(2+) responses. The effect of general PDE or PDE3 inhibition was accompanied by an increase in cAMP, and potentiated by Gs stimulation with prostaglandin E(1). In platelet-rich plasma, general or PDE3 inhibition blocked platelet aggregation, integrin activation, secretion and thrombin generation. In contrast, inhibition of PDE5 increased the cGMP level, but without significant influence on aggregation, alphaIIbbeta3 activation, secretion or procoagulant activity. Nitroprusside (nitric oxide) potentiated the effect of PDE5 inhibition in elevating cGMP. Nitroprusside inhibited platelet responses, but this was accompanied by elevation of cAMP. Together, these results indicate that cAMP is persistently formed in platelets, independently of agonist-induced Gs stimulation. PDE3 thus functions to keep cAMP at a low equilibrium level and reduce the cAMP-regulated threshold for platelet activation. This crucial role of PDE3, but not of PDE5, extends to all major processes in thrombus formation: assembly of platelets into aggregates, secretion of autocrine products, and procoagulant activity.
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PMID:Control of platelet activation by cyclic AMP turnover and cyclic nucleotide phosphodiesterase type-3. 1504 73


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