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 factor (ANF) is a collective term used to describe a group of peptides isolated from mammalian atria which have vasorelaxant activity as well as diuretic and natriuretic activity. Recently, ANF peptides have been shown to bind to specific receptors on vascular smooth muscle cells (VSMC) and to cause an elevation in cGMP levels. We have previously demonstrated that VSMC possess a prominent, cyclic-nucleotide-sensitive Na/K/Cl cotransport system. In the present study, the effects of the ANF peptide rat atriopeptin III (rAP III) were measured on Na/K/Cl cotransport of VSMC by using primary cultures derived from rat thoracic aorta. It was found that rAP III caused a marked elevation of Na/K/Cl cotransport. Maximal stimulation occurred at 100 nM, and the dose of rAP III required for half-maximal potassium influx (K1/2) was 9 nM. We also investigated the effect of rAP III on cGMP levels in VSMC. It was found that rAP III increased cGMP in a dose-dependent manner, with a K1/2 value of 10 nM. Finally, we measured the effect of the permeable cGMP analog 8-bromo-cGMP on Na/K/Cl cotransport. It was found that 8-bromo-cGMP stimulated cotransport to the same extent as did a saturating dose of rAP III (K1/2 = 0.2 microM). Saturating doses of rAP III and 8-Br-cGMP in combination did not stimulate cotransport in an additive manner, suggesting that rAP III probably does not elevate cGMP via inhibition of phosphodiesterase. These findings suggest that activation of Na/K/Cl cotransport via elevations in cGMP may be associated with ANF-mediated vasorelaxation and/or ANF-mediated diuresis and natriuresis.
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PMID:Atrial natriuretic factor stimulates Na/K/Cl cotransport in vascular smooth muscle cells. 294 44

Atrial natriuretic peptide (ANP) induces potent diuretic/natriuretic, vasorelaxing and aldosterone inhibitory effects. Increased plasma levels in congestive heart failure (CHF) have been reported. The aim of this study was to investigate plasma immunoreactive ANP (ir-ANP) levels during acute treatment of CHF. Seven patients with CHF underwent cardiac catheterization. Ir-ANP plasma levels were followed up to two h after administration of an orally given phosphodiesterase inhibitor (Milrinone); a substance with positive inotropic and peripheral vasodilating properties. In all patients cardiac output increased and cardiac filling pressures decreased markedly. Initially high ir-ANP plasma levels decreased. Our patients did not have an increased blood volume. It is concluded that plasma ir-ANP levels in the pulmonary artery rapidly decrease when atrial pressure is reduced. These data suggest that atrial pressure is the major determinant for release of ir-ANP in man and that the ability to respond quickly to changes in cardiac filling pressures is maintained in patients with severe CHF. Plasma ir-ANP levels may also become useful as an index of the degree of heart failure and serve as a tool in monitoring response to drug therapy.
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PMID:Atrial natriuretic peptide during acute treatment of congestive heart failure. 296 29

Recently an inhibitory effect of atrial natriuretic factor (ANF) on the adenylate cyclase system has been reported in vascular tissue. In seeking similar affects in renal tissue, we studied the effect of ANF on cyclic AMP levels in single nephron segments and in glomeruli from the rat. Individual nephron segments or glomeruli were incubated in the presence of a phosphodiesterase inhibitor, with or without parathyroid hormone (PTH) or arginine vasopressin (AVP) and varying concentrations of ANF at 37 degrees C for 2 min. The capacity for alpha 2-adrenoceptor inhibition of adenylate cyclase was demonstrated in the proximal convoluted tubule, cortical collecting tubule and in glomeruli. Nevertheless, ANF could not inhibit cAMP formation in any of these nephron segments nor in the glomerulus. Thus, unlike the vasculature, ANF has no inhibitory effect on cAMP formation in these renal tissues.
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PMID:Lack of inhibition by atrial natriuretic factor on cyclic AMP levels in single nephron segments and the glomerulus. 298 66

Guanosine cyclic 3':5'-monophosphate (cGMP) plays a crucial role in regulating vascular smooth muscle contractile state. In rat aortic smooth muscle cells (RSMC) three isozymes of phosphodiesterase (PDE) may be involved in the degradation of cGMP, namely PDE I, PDE III, and PDE V. To study the effective contribution of PDE V to the control of intracellular cGMP levels, a specific and potent PDE V inhibitor 1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazolo[3, 4d]- pyrimidin-4-(5H)-one (DMPPO) was synthesized. DMPPO is a competitive inhibitor with respect to cGMP (Ki = 3 nM) and displayed high selectivity for PDE V as compared to other PDE isozymes. DMPPO strongly potentiated the cGMP response of atrial natriuretic peptide- or sodium nitroprusside-treated RSMC (EC50 = 0.5 microM). In addition, similar intracellular cGMP levels were obtained in the presence of a saturating concentration of DMPPO or 3-isobutyl-1-methylxanthine, a nonspecific PDE inhibitor, suggesting that cGMP is almost exclusively hydrolyzed by PDE V in RSMC. Stimulation of RSMC with atrial natriuretic factor resulted in accumulation of cGMP in the extracellular media. This egression was shown to be proportional to the intracellular level of cGMP and a first-order rate constant of 0.04 min-1 was determined for the egression process. DMPPO did not interfere with the efflux and allowed us to show that intracellular cGMP levels are mainly controlled by PDE V, rather than by egression in RSMC. DMPPO is, therefore, a useful tool for determining the role of PDE V in the control of cGMP levels in living cells and tissues.
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PMID:Characterization of a novel potent and specific inhibitor of type V phosphodiesterase. 750 59

Bovine aortic endothelial cells contain cyclic GMP-stimulated phosphodiesterase (PDE) regulating intracellular cyclic AMP and cyclic GMP levels. To investigate the roles of this PDE isoform for cyclic AMP hydrolysis in intact endothelial cells (EC), we used an adenine prelabeling method to determine cyclic AMP accumulation in response to agents that might produce effects that increase cyclic GMP levels. Atrial natriuretic peptide (ANP), which dramatically increased cyclic GMP accumulation, reduced cyclic AMP in cultured EC from bovine aorta with or without addition of L-isoproterenol (L-ISO), whereas sodium nitroprusside (SNP) and 8-bromo cyclic GMP had no effect. The reduction in cyclic AMP by ANP was dose dependent (> or = 1.0 nM) and rapid (significant reduction was induced in < or = 15 s) and was abolished when EC were preincubated with 3-isobutyl-1-methylxanthine (IBMX) and HL-725, both nonselective PDE inhibitors. ANP had no effects on adenylate cyclase activity, nor any direct effects on the activities of partially purified cyclic GMP-stimulated PDE isoform or cyclic AMP-specific isoform. However, cyclic AMP hydrolyzing activities of EC were enhanced when EC were pretreated with 0.1 microM ANP. ANP activates cyclic GMP-stimulated PDE and induces reduction of cyclic AMP accumulation in intact EC, which may modify cyclic GMP-dependent endothelial function involved in ANP.
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PMID:Atrial natriuretic peptide reduces cyclic AMP by activating cyclic GMP-stimulated phosphodiesterase in vascular endothelial cells. 752 89

Atrial natriuretic factor (ANF) inhibits fluid absorption (Jv) in the proximal straight tubule (PST) only after stimulation with angiotensin II (ANG II). To investigate ANF's dependency on ANG II for transport inhibition, we blocked and mimicked angiotensin's second messenger cascades and then examined ANF's ability to inhibit Jv. ANG II (10(-10) M)-stimulated Jv was 0.47 +/- 0.10 nl.mm-1. min-1. After ANF (10(-10) M) was added to the bath, Jv fell by approximately 40% (P < 0.05). ANG II stimulates Jv via activation of protein kinase C (PKC) and decreasing protein kinase A (PKA) activity. We inhibited PKA with H-89. In the presence of only H-89, Jv was 0.75 +/- 0.11 nl.mm-1.min-1. After ANF was added to the bath Jv fell by 30% (P < 0.05). Intracellular adenosine 3',5'-cyclic monophosphate content was not affected by ANF in the presence of ANG II. ANF could not inhibit Jv in the presence of ANG II and 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor. KT-5823, a guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase inhibitor, blocked the action of ANF on Jv (P > 0.30). PKC inhibition did not prevent the decrease in Jv induced by ANF. We conclude that ANF inhibits ANG II-induced stimulation of transport by a mechanism that requires phosphorylation mediated by cGMP-dependent protein kinase subsequent to a decrease of PKA activity.
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PMID:ANF and angiotensin II interact via kinases in the proximal straight tubule. 753 66

The pathophysiology of heart failure is closely associated with neuroendocrine changes. Activation of these humoral systems apparently serves as a compensatory mechanism for the failing circulation. However, overshoot of such mechanisms may further depress cardiac function by increasing afterload, resulting in a vicious cycle of reflex neuroendocrine activation. Corollary decreases in renal function activate the renin-angiotensin-aldosterone system as well, which further contributes to the cycle of downward-spiralling cardiac function. Many hormonal factors are increased in congestive heart failure. While some influences are vasodilatory, the net effect is marked vasoconstriction. The level of activation of these systems apparently corresponds to the severity of heart failure. Furthermore, elevated levels of these hormones, including norepinephrine, atrial natriuretic factor, plasma renin, and plasma arginine vasopressin, may play a more direct role in worsening heart failure. In fact, elevated catecholamine levels are directly related to prognosis. Catecholamines increase myocardial oxygen demand and are also arrhythmogenic. Oral catecholamines and phosphodiesterase inhibitors, which work by similar mechanisms, have yielded increased mortality rates in heart failure trials. In contrast, mortality rates are reduced in patients treated with angiotensin-converting enzyme inhibitors. Thus, it is clear that neuroendocrine changes are not only a marker of the severity of heart failure, but also directly worsen it. Interventions that antagonize or diminish these neuroendocrine changes apparently benefit patients with heart failure.
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PMID:Neuroendocrine changes in heart failure and their clinical relevance. 758 61

Atrial natriuretic factor (ANF) has been demonstrated to be effective in the treatment of acute renal failure (ARF) in both rat and humans. The biological effects of ANF are presumed to be mediated by the generation of intracellular 3',5'-cyclic guanosine monophosphate (cGMP). Therefore, the current investigation examined whether zaprinast (M&B 22948), a guanosine 3',5'-cyclic monophosphate (cGMP)-specific phosphodiesterase inhibitor, would be effective in the treatment of established acute renal failure in the rat. Acute renal failure was induced by 60 minutes of bilateral renal artery clamping. Twenty-four hours after the ischemic insult, rats received either vehicle (5% Dextrose), zaprinast (0.03 or 0.3 mg/kg/min) or ANF24 (0.2 micrograms/kg/min) intravenously for four hours. Renal function, as measured by daily serum creatinine (days 1 to 7) and day 2 inulin clearances, was dramatically improved by zaprinast but not ANF treatment. Forty-eight hours post-renal ischemia, glomerular filtration rate (GFR) was 0.14 +/- 0.04 (ml/min/100 g body wt) in the vehicle and 0.94 +/- 0.29 in the zaprinast treated animals. To evaluate the mechanism by which zaprinast accelerated renal recovery, we measured regional blood flow in the postischemic rat kidneys during drug treatment with a laser doppler flowmeter. Both high and low dose zaprinast significantly increased cortical (17%) and outer medullary blood flow (40% and 60%), an effect not seen with ANF. In summary, zaprinast is effective in the treatment of established ischemic ARF. The mechanism by which zaprinast accelerates renal recovery is due to its unique ability to stimulate regional renal blood flow and increase intracellular cGMP in the setting of tissue ischemia.
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PMID:Zaprinast accelerates recovery from established acute renal failure in the rat. 764 25

We characterized cyclic nucleotide phosphodiesterases isolated from rat mesangial cells and assessed their roles in regulating cellular cyclic nucleotide levels. Three peaks of phosphodiesterase activity were eluted by a linear sodium acetate gradient from a Q Sepharose column loaded with the mesangial cell extract. The first peak activity was stimulated by Ca(2+)-calmodulin and inhibited by calmodulin-stimulated phosphodiesterase inhibitors but not by a selective cGMP specific phosphodiesterase V inhibitor. The second, minor activity peak was stimulated by cyclic GMP and inhibited by EHNA [erythro-9-(2-hydroxy-3-nonyl)-adenine], a selective inhibitor of cyclic GMP-stimulated phosphodiesterase II. The last peak activity was not inhibited by cyclic GMP but selectively inhibited by rolipram [4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidene] or Ro 20-1724 [4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone], inhibitors of cyclic AMP specific, cyclic GMP insensitive phosphodiesterase IV. Based on their order of chromatographic elution, kinetic properties and sensitivity to allosteric agents and inhibitors, the peak 1, 2 and 3 correspond to phosphodiesterase I, II and IV. The basal cyclic GMP level was raised more effectively by selective inhibitor of phosphodiesterase I than phosphodiesterase II. In contrast, the atrial natriuretic factor-induced cyclic GMP elevation was potentiated more effectively by selective inhibitors of phosphodiesterase II than phosphodiesterase I. The forskolin-induced cyclic AMP increase was greatly potentiated by selective phosphodiesterase IV inhibitors but not by other phosphodiesterase inhibitors. These data suggest that phosphodiesterase I and II are responsible for cyclic GMP hydrolysis whereas phosphodiesterase IV is mainly responsible for cyclic AMP hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic nucleotide phosphodiesterase isozymes in rat mesangial cells. 778 11

Previous studies have demonstrated that cGMP and cAMP reduce the endothelial permeability for fluids and macromolecules when the endothelial permeability is increased by thrombin. In this study, we have investigated the mechanism by which cGMP improves the endothelial barrier function and examined whether nitric oxide (NO) can serve as an endogenous modulator of endothelial barrier function. Thrombin increased the passage of macromolecules through human umbilical vein and human aortic endothelial cell monolayers and concomitantly increased [Ca]2+ in vitro. Inhibition of these increases by the intracellular Ca2+ chelator BAPTA indicated that cytoplasmic Ca2+ elevation contributes to the thrombin-induced increase in endothelial permeability. The cGMP-dependent protein kinase activators 8-bromo-cGMP (8-Br-cGMP) and 8-(4-chlorophenylthio)cGMP (8-PCPT-cGMP) decreased the thrombin-induced passage of macromolecules. Two pathways accounted for this observation. Activation of cGMP-dependent protein kinase by 8-PCPT-cGMP decreased the accumulation of cytoplasmic Ca2+ in aortic endothelial cells and hence reduced the thrombin-induced increase in permeability. On the other hand, in umbilical vein endothelial cells, cGMP-inhibited phosphodiesterase (PDE III) activity was mainly responsible for the cGMP-dependent reduction of endothelial permeability. The PDE III inhibitors Indolidan (LY195115) and SKF94120 decreased the thrombin-induced increase in permeability by 50% in these cells. Thrombin treatment increased cGMP formation in the majority of, but not all, cell cultures. Inhibition of NO production by NG-nitro-L-arginine methyl ester (L-NAME) enhanced the thrombin-induced increase in permeability, which was restricted to those cell cultures that displayed an increased cGMP formation after addition of thrombin. Simultaneous elevation of the endothelial cGMP concentration by atrial natriuretic factor, sodium nitroprusside, or 8-Br-cGMP prevented the additional increase in permeability induced by L-NAME. These data indicate that cGMP reduces thrombin-induced endothelial permeability by inhibition of the thrombin-induced Ca2+ accumulation and/or by inhibition of cAMP degradation by PDE III. The relative contribution of these mechanisms differs in aortic and umbilical vein endothelial cells. NO can act in vitro as an endogenous permeability-counteracting agent by raising cGMP in endothelial cells of large vessels.
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PMID:cGMP and nitric oxide modulate thrombin-induced endothelial permeability. Regulation via different pathways in human aortic and umbilical vein endothelial cells. 783 30


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