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)

Clearance studies were made to determine the influence of intravenous infusions of dopamine (between 2.5 and 3.5 mug.kg.-1min.-1) on renal function and on the adenyl cyclase phosphodiesterase system in eleven patients with chronic renal disease. Glomerular filtration rate (+ 19%), effective renal plasma flow )+ 29%), sodium (+ 199%) and potassium (+ 40%) clearances were significantly increased. These effects were associated with a stimulation of the adenyl cyclase phosphodiesterase system demonstrated by an increase of cyclic adenosine 3'5'-monophosphate in plasma and urine. The results suggest that dopamine probably affects renal function by activating the adenyl cyclase phosphodiesterase system.
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PMID:Effects of dopamine on kidney function and on the adenyl cyclase phosphodiesterase system in man. 17 93

Renal failure after cardiac surgery using cardiopulmonary bypass (CPB) is well understood for infants, children and adults. The perioperative risk factors after CPB for immature kidneys in newborns are not well known. This retrospective study investigates perioperative risk factors for renal insufficiency in neonates. I) Preoperative: Age; weight, performed angiography, amount of dye used in angiography, renal disease and creatinine. II) Intraoperative: Duration of operation, duration of MAP < 40 mmHg, use of deep hypothermia, in-out fluid balance, duration of CPB, duration of circulatory arrest and cross-clamp time. III) Postoperative: Creatinine, use of catecholamines, use of nitroglycerine (NG) or phosphodiesterase inhibitors (PDI) and additional antibiotics. From Jan. 1990 to Dec. 1994 50 neonates underwent cardiac surgery using CPB (n = 23 transposition of the great arteries; n = 4 pulmonary atresia; n = 6 critical pulmonary stenosis; n = 5 hypoplastic left heart syndrome; n = 3 Ebstein's anomaly; n = 2 interrupted arch with hypoplastic left ventricle; n = 2 single ventricle; n = 1 each: double outlet right ventricle, tricuspid atresia, critical aortic stenosis, rhabdo-myosarkoma, corrected transposition of the great arteries.) Thirty-one patients entered the study. Depending on the postoperative creatinine level two groups (group I: creatinine <1 mg/dl and group II: >1 mg/dl) were created. The diureses between the two groups did not differ. Comparing the patients of group I vs. group II, patients of group I were younger (mean age: 7.7 d. vs. 11.4 d), lighter (mean weight: 3260 g vs. 3430 g), less had angiography (44% vs. 77%), received more dye (mean amount: 14 ml vs. 7 ml), the duration of MAP < 40 mmHg while on CPB was longer (mean duration 3 min vs. 21 min), more patients were operated on using deep hypothermia (55% vs. 27%), the postoperative in-out-fluid balance was more positive (mean balance +413 ml vs. +221 ml), received postop. more frequently high doses of catocholamines and less common NG or PDI, but more often additional antibiotics. The duration of circulatory arrest (mean time: 60 min vs. 55 min) and cross clamp time (mean time: 68 min vs. 65 min) seems not to be a risk factor and vasodilators given simultaneously with catecholamines may have preventive effects on postoperative renal insufficiency. Immature kidneys may play an outstanding role in the susceptibility of damaging factors. Further investigation with a larger number of patients allowing to obtain statistical significant risk factors are required.
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PMID:Renal insufficiency in neonates after cardiac surgery. 883 54

Blunted volume expansion (VE) natriuresis and renal resistance to atrial natriuretic peptide (ANP) characterize states of pathological sodium retention. This study examined rats 1 to 3 wk after common bile-duct ligation (CBDL), at which time they had hyperbilirubinemia and hypoalbuminemia. Sham-operated normal rats (Sham) showed an increased sodium excretion rate (UNaV) from 1.0 +/- 0.1 to 16.3 +/- 3.9 muEq/min in response to acute VE (iv saline, 2 mL/100 g body wt over 5 min), whereas CBDL rats had a blunted response that was apparent after 1 wk and became maximal at 2 and 3 wk (0.3 +/- 0.1 to 3.2 +/- 0.4 muEq/min at 3 wk, P < 0.01 versus Sham response). The peak urinary cGMP excretion rate (UcGMPV) was also blunted (37.9 +/- 3.6 versus 87.5 +/- 8.3 pmol/min, P < 0.01) despite an even greater increase in plasma ANP concentration (Sham, 9.6 +/- 0.4 pg/mL in hydropenia to 22.8 +/- 2.6 pg/mL after VE; CBDL, 15.3 +/- 2.3 to 41.8 +/- 6.8 pg/mL). ANP-dependent cGMP accumulation by isolated inner medullary collecting duct (IMCD) cells from both Sham and CBDL rat kidneys was dose-dependent; however, at higher concentrations of ANP (> 10(-8) M), accumulation by cells from CBDL rats was significantly blunted, indicating resistance to ANP. Binding of 125I-ANP to IMCD cells was not different in CBDL rats compared with Sham control rats. Renal denervation improved but did not completely reverse the blunted natriuresis, and ANP resistance persisted in IMCD cells from denervated kidneys of CBDL rats. Incubation of IMCD cells with the phosphodiesterase inhibitors isomethylbutylxanthine or Zaprinast (each at 10(-3) M) restored ANP responsiveness in both innervated and denervated kidneys from CBDL rats, and intrarenal infusion of Zaprinast (10 micrograms/min) corrected the blunted increase in UNaV and UcGMPV after VE in rats with CBDL. These results suggest that ANP resistance in a model of abnormal sodium metabolism devoid of intrinsic renal disease may be related to increased activity of phosphodiesterase in renal target cells for ANP as well as to heightened renal nerve activity.
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PMID:Mechanisms contributing to renal resistance to atrial natriuretic peptide in rats with common bile-duct ligation. 891 70

Theophylline, a drug that has been used for several decades, has several different actions at a cellular level, including inhibition of phosphodiesterase isoenzymes, antagonism of adenosine, enhancement of catecholamine secretion, and modulation of calcium fluxes. Recently, theophylline was found to have several immunomodulatory and anti-inflammatory properties, and thus interest in its use in patients with asthma has been renewed. The use of theophylline in the treatment of asthma and chronic obstructive pulmonary disease has diminished with the advent of new medications, but theophylline remains beneficial, especially in the patient with difficult refractory symptoms. In the future, theophylline may be used as treatment for bradyarrhythmias after cardiac transplantation, prophylactic medication to reduce the severity of nephropathy associated with intravenous administration of contrast material, therapy for breathing problems during sleep, and treatment for leukemias.
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PMID:Theophylline: recent advances in the understanding of its mode of action and uses in clinical practice. 955 39

A polymorphism in the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1) (previously known as PC-1), resulting in an amino acid change from lysine to glutamine at codon 121 (K121Q), is associated with insulin resistance. A small follow-up study of patients with type 1 diabetes and proteinuria found that renal function declines more rapidly in carriers of the Q variant than in noncarriers. To examine this finding further, we conducted a large case-control study and a family-based study. Genomic DNA was obtained from 659 patients: 307 with normal urinary albumin excretion despite diabetes duration of >15 years (control subjects) and 352 with advanced diabetic nephropathy, of whom 200 had persistent proteinuria and 152 had end-stage renal disease (ESRD). Individuals were genotyped for Q and K variants using a previously described protocol. The frequency of Q variant carriers was 21.5% in control subjects, 31.5% in subjects with proteinuria, and 32.2% in subjects with ESRD (P = 0.012). In a stratified analysis according to duration of diabetes, the risk of early-onset ESRD for carriers of the Q variant was 2.3 times that for noncarriers (95% CI, 1.2-4.6). The Q variant was not associated with late-onset ESRD. Similar findings were obtained in a family-based study. We conclude that carriers of the Q variant of ENPP1 are at increased risk for developing ESRD early in the course of type 1 diabetes.
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PMID:Polymorphism in ecto-nucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1/PC-1) and early development of advanced diabetic nephropathy in type 1 diabetes. 1191 43

Previous studies have reported that pentoxifylline, a phosphodiesterase inhibitor, attenuates experimental mesangial proliferative glomerulonephritis. This study hypothesized that pentoxifylline could also attenuate the renal disease progression in rats with remnant kidney. After 5/6 subtotal nephrectomy, rats developed progressively elevated proteinuria and plasma creatinine, glomerulosclerosis, interstitial inflammation, and fibrosis, all of which were attenuated by 40 to 60% by pentoxifylline. However, the elevated BP was not changed by pentoxifylline. Pentoxifylline reduced the upregulation of monocyte chemoattractant protein-1 gene by 60% in the cortex of remnant kidney, as well as in a dose-dependent manner in the albumin- or angiotensin II-stimulated proximal tubular cells. It also reduced the upregulation of mitogenic and profibrogenic genes by 50%, including platelet-derived growth factor, fibroblast growth factor-2, transforming growth factor-beta(1), connective tissue growth factor, and types I and III collagen in the cortex of remnant kidney. Furthermore, pentoxifylline was found to decrease the numbers of interstitial myofibroblasts by 60% in the cortex of remnant kidney and suppress the proliferation of cultured interstitial fibroblasts. It also reduced the angiotensin II-induced or transforming growth factor-beta(1)-induced expression of connective tissue growth factor gene in cultured fibroblasts and mesangial cells. Combining pentoxifylline with an angiotensin-converting enzyme inhibitor, cilazapril, almost completely attenuated the renal disease progression in rats with remnant kidney. In conclusion, pentoxifylline alone can attenuate the chronic renal disease progression. Its combination with cilazapril has the potential to prevent the renal disease progression almost completely.
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PMID:Pentoxifylline attenuated the renal disease progression in rats with remnant kidney. 1244 23

We evaluated association between hyperinsulinemia/insulin resistance and microalbuminuria in the insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rat. OLETF rats showed glomerular hyperfiltration (an increase in creatinine clearance and a decrease in fractional excretion of Na) and microalbuminuria at the insulin-resistant prediabetic stage, and both were related to expression of transforming growth factor (TGF)-beta(1) and extracellular matrix protein such as fibronectin and collagen (a(1)) IV. Cilostazol, a selective type III cyclic nucleotide phosphodiesterase (PDE) inhibitor, normalized glomerular hyperfiltration and microalbuminuria with a parallel decline of TGF-beta(1) and extracellular matrix protein mRNA expression. Cilostazol may be beneficial to lessen early glomerular nephropathy in a state of hyperinsulinemia/insulin resistance.
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PMID:Cilostazol, a phosphodiesterase inhibitor, reduces microalbuminuria in the insulin-resistant Otsuka Long-Evans Tokushima Fatty rat. 1553 93

Monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor (TGF)-beta1 are critical mediators of renal injury by promoting excessive inflammation and extracellular matrix deposition, thereby contributing to progressive renal disease. In renal disease models, MCP-1 stimulates the production of TGF-beta1. However, a potential role for TGF-beta1 in the regulation of MCP-1 production by mesangial cells (MCs) has not previously been evaluated. The objectives of this study were to define the role of TGF-beta1 in regulation of MCP-1 expression in cultured MCs and to define mechanisms through which rolipram (Rp), a phosphodiesterase isoenzyme 4 (PDE4) inhibitor with anti-inflammatory properties, alters MCP-1 expression. TGF-beta1 induced MCP-1 in a time- and dose-dependent manner without increasing transcription of the MCP-1 gene. TGF-beta1-mediated induction of MCP-1 occurred without activation of the NF-kappaB pathway. Rp blocked TGF-beta1-stimulated MCP-1 expression via a protein kinase A-dependent process, at least in part, by decreasing MCP-1 message stability. Rp exerted no effect on activation of the Smad pathway by TGF-beta1. TGF-beta1-mediated induction of MCP-1 required activation of ERK and p38, both of which were suppressed by a PDE4 inhibitor. TGF-beta1-stimulated reactive oxygen species (ROS) generation by MCs, and Rp inhibited ROS generation in TGF-beta1-stimulated MCs; in addition, both Rp and ROS scavengers blocked TGF-beta1-stimulated MCP-1 expression. We conclude that TGF-beta1 stimulates MCP-1 expression through pathways involving activation of ERK, p38, and ROS generation. Positive cross-talk between TGF-beta1 and MCP-1 signaling in MCs may underlie the development of progressive renal disease. Rp, by preventing TGF-beta1-stimulated MCP-1 production, may offer a therapeutic approach in retarding the progression of renal disease.
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PMID:TGF-beta1 stimulates monocyte chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase isoenzyme 4-dependent process. 1593 Jan 46

Treatment of aging men and women with testosterone supplements is increasing. The supplements are given to postmenopausal women mainly to improve their libido and to aging men to improve muscle mass and bone strength, to improve libido and quality of life, to prevent and treat osteoporosis, and, with the phosphodiesterase-5 inhibitors, such as sildenafil, to treat erectile dysfunction. The increased use of testosterone supplements in aging individuals has occurred despite the fact that there have been no rigorous clinical trials examining the effects of chronic testosterone on the cardiovascular-renal disease risk. Studies in humans and animals have suggested that androgens can increase blood pressure and compromise renal function. Androgens have been shown to increase tubular sodium and water reabsorption and activate various vasoconstrictor systems in the kidney, such as the renin-angiotensin system and endothelin. There is also evidence that androgens may increase oxidative stress. Furthermore, the kidney contains the enzymes necessary to produce androgens de novo. This review presents an overview of the data from human and animal studies in which the role of androgens in promoting renal and cardiovascular diseases has been investigated.
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PMID:Testosterone supplementation in aging men and women: possible impact on cardiovascular-renal disease. 1621 Apr 52

HIV-associated nephropathy is characterized by renal podocyte proliferation and dedifferentiation. This study found that all-trans retinoic acid (atRA) reverses the effects of HIV-1 infection in podocytes. Treatment with atRA reduced cell proliferation rate by causing G1 arrest and restored the expression of the differentiation markers (synaptopodin, nephrin, podocin, and WT-1) in HIV-1-infected podocytes. It is interesting that both atRA and 9-cis RA increased intracellular cAMP levels in podocytes. Podocytes expressed most isoforms of retinoic acid receptors (RAR) and retinoid X receptors (RXR) with the exception of RXRgamma. RARalpha antagonists blocked atRA-induced cAMP production and its antiproliferative and prodifferentiation effects on podocytes, suggesting that RARalpha is required. For determination of the effect of increased intracellular cAMP on HIV-infected podocytes, cells were stimulated with either forskolin or 8-bromo-cAMP. Both compounds inhibited cell proliferation significantly and restored synaptopodin expression in HIV-infected podocytes. The effects of atRA were abolished by Rp-cAMP, an inhibitor of the cAMP/protein kinase A pathway and were enhanced by rolipram, an inhibitor of phosphodiesterase 4, suggesting that the antiproliferative and prodifferentiation effects of atRA on HIV-infected podocytes are cAMP dependent. Furthermore, both atRA and forskolin suppressed HIV-induced mitogen-activated protein kinase 1 and 2 and Stat3 phosphorylation. In vivo, atRA reduced proteinuria, cell proliferation, and glomerulosclerosis in HIV-1-transgenic mice. These findings suggest that atRA reverses the abnormal phenotype in HIV-1-infected podocytes by stimulating RARalpha-mediated intracellular cAMP production. These results demonstrate the mechanism by which atRA reverses the proliferation of podocytes that is induced by HIV-1.
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PMID:Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway. 1718 84


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