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)

Phosphodiesterase I (PDE I) is an exonuclease capable of hydrolyzing a variety of phosphate ester and pyrophosphate bonds. Cell fractionation and histochemical studies in animal tissues have localized PDE I in the plasma membrane of various epithelia. This suggests a role for the enzyme in active transport. Distribution of PDE I in human tissues has not previously been studied. We have produced a polyclonal antiserum to bovine intestinal PDE I and have demonstrated crossreactivity with the human intestinal enzyme. This polyclonal antiserum was used in PAP immunocytochemistry to localize immunoreactive PDE I in a variety of human tissues. Localization was prominent in the gastrointestinal tract, including the cytoplasm of gastric mucosa parietal cells, cytoplasm of surface epithelium and isolated crypt cells in small intestine, and the colonic epithelial cytoplasm and brush border. Parotid gland acinar cells and scattered ductal cells showed positive cytoplasmic staining. Acinar and scattered pancreatic islet cells contained immunoreactive PDE I, as did Kupffer cells of the liver sinusoids. Immunoreactive PDE I was found in all vascular endothelia. The epithelium of the urinary tract showed extensive immunoreactivity. This included the distal convoluted and collecting tubules of the kidney, and ureteral and bladder urothelium. In previous histochemical studies of animal tissues, no evidence of PDE I activity was noted in male or female reproductive tract. In this study, immunoreactive PDE I was localized to human Sertoli cells and to basal epithelium of the epididymis and prostate acini. Fallopian tube epithelium of female reproductive tract also demonstrated immunoreactive PDI I, as did several cell types in term placenta. Our immunocytochemical results with human tissues differ significantly from previous histochemical studies in animal tissues, principally in the genitourinary system. This may be due in part to the different detection systems employed as well as the higher sensitivity of the immunoperoxidase technique. This underscores the importance of adjunct techniques in tissue surveys. The widespread epithelial distribution of immunoreactive PDE I detected by this polyclonal antibody implies an integral role in cell function, probably in active transport.
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PMID:Distribution of phosphodiesterase I in normal human tissues. 302 90

Ventricular arrhythmias and disturbed autonomic control, as reflected by abnormal heart rate variability (HRV), are related to hemodynamic impairment in chronic heart failure (CHF). We investigated the effects of orally (p.o.) administered isomazole, a new phosphodiesterase (PDE) inhibitor with calcium-sensitizing properties, on hemodynamics, ventricular arrhythmias, and HRV and examined a possible interaction between these parameters. Hemodynamic measurements and ambulatory ECG monitoring were performed in 12 patients with stable CHF class III-IV after single doses of isomazole 5-30 mg. Pulmonary wedge pressure decreased after 5, 10, 20, and 30 mg, but cardiac output, (CO) increased only after the higher doses [20 mg, + 20% (p = 0.031)] of isomazole. HR did not change. Mean arterial and pulmonary artery pressure, (MAP, PAP) decreased significantly in the 10- and 20-mg groups [10 mg, -6% (p = 0.035) and -14% (p < 0.001) respectively; 20 mg, -13% (p = 0.047) and -31% (p = 0.006), respectively]. Isomazole did not exert a significant effect on ventricular arrhythmias in the subsequent 24 h after acute dosing. Analysis of HRV showed that rMSSD and pNN50 (parameters of vagal tone) tended to increase after isomazole administration. Normalized high-frequency power during the day increased from 17.4 to 22.3 nu (p < 0.05), whereas low frequency tended to decrease from 52.7 to 48.2 nu (p = 0.06). Acute isomazole administration improves hemodynamics but has no effect on ventricular arrhythmias. The HRV variability data suggest development of an increase in vagal control of HR, parallel to the acute hemodynamic improvement after isomazole. Withdrawal of vagal control of HR in CHF may be a reversible process.
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PMID:Exploratory study of the effects of single doses of isomazole on hemodynamics and heart rate variability parameters in chronic heart failure. 772 57

The greater part of the intracellular aminopeptidases in Pseudomonas aeruginosa and Acinetobacter calcoaceticus is soluble. The localization of aminopeptidases in the cells was examined using the osmotic shock method with some modifications. When the cells of A. calcoaceticus and P. aeruginosa of the logarithmic phase were subjected to an osmotic shock, all aminopeptidases investigated were mainly localized in the sucrose supernatants and in the periplasm. Acid phosphatase as marker enzyme for periplasm showed a similar distribution between the fractions as the aminopeptidases. The periplasmic aminopeptidases of both microorganisms were separated by FPLC on Superose 12 and their molecular masses were determined. The results obtained show that at least four different aminopeptidases occur in the periplasm, a leucyl aminopeptidase (LAP, cleaving Leu-NH-NH2, 400 kDa), a glutamyl aminopeptidase (GAP, 200 kDa), an alanyl aminopeptidase (AAP, 80 kDa) and a prolyl aminopeptidase (PAP, 65 kDa). The results are in agreement for both species. Our results show clearly that aminopeptidases of these typical members of Gram-negative bacteria are mainly periplasmic like degrading enzymes (alkaline and acid phosphatases, 5'-nucleotidase, cyclic phosphodiesterase), detoxifying enzymes and binding proteins for amino acids and sugars.
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PMID:Periplasmic aminopeptidases in Acinetobacter calcoaceticus and Pseudomonas aeruginosa. 822 72

Cardiopulmonary bypass (CPB) produces an inflammatory response due to the interaction of blood with a foreign body surface. The lungs are most affected by this inflammatory response. Pentoxifylline (PTX), a phosphodiesterase inhibitor and an inhibitor of leukocyte activation, is used to minimize damage in lungs where leukocytes play an important role. Twenty patients with mitral valve stenosis with planned mitral valve surgery were included in the study. The ten patients receiving pentoxifylline (PTX group) were administered 400 mg PTX orally TID for 3 days preoperatively and, following anesthetic induction, a 300 mg PTX infusion was given. The ten patients receiving no PTX were the control group (CT). Platelet and leukocyte counts, mean pulmonary arterial pressure (mPAP), pulmonary capillary wedge pressure (PCWP), cardiac index (CI), pulmonary vascular resistance (PVR), alveolar-arterial PO2 gradient (AaDO2) were measured just before and after CPB, and 2 h postoperatively. The number of the leukocytes increased in the blood samples drawn 15 min after CPB in both groups and 2 h postoperatively showed no statistical change. The number of platelets had decreased significantly at the end of the CPB in both groups and, 2 h postoperatively, there was a further decrease in the blood count in the control group (P < 0.05). There was no significant difference in either the preoperative or postoperative PAP, PAWP, and CI. Pulmonary vascular resistance increased in both groups following the CPB (CT, before: 136 +/- 44, after: 177 +/- 94 dyne. sec.cm-5; PTX, before: 151 +/- 82, after 182 +/- 43 dynes.sec.cm-5). Two hours postoperatively, a considerable increase continued in the control group (CT 219 +/- 170 dynes.sec. cm-5), while there was an insignificant increase in the PTX group (PTX 193 +/- 51 dynes.sec.cm-5) (P < 0.05). The alveolar-arterial PO2 gradient increased after the CPB in both groups but a moderate decrease was observed 2 h postoperatively. In lung biopsy specimens taken before and after the CPB, there was marked leukocyte sequestration in the control group, whereas the number of leukocytes was seen to be insignificant in the PTX group (P < 0.005). This dosage regimen of PTX inhibits the postoperative increase in PVR and greatly minimized leukocyte sequestration in the lung due to CPB.
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PMID:The effect of pentoxifylline on the lung during cardiopulmonary bypass. 873 90

A new dual-action drug called saterinone combines both alpha-1 blocking vasodilatory property and phosphodiesterase III inhibition--mediated inotropism. A placebo-controlled, randomized, double-blind study was performed in 12 patients with severe congestive heart failure. Either 2 &mgr;g center dot kg center dot min(minus sign1) saterinone (n = 8) or placebo (n = 4) was injected intravenously over 3 h at rest. On-line hemodynamic measurement utilizing intra-arterial blood pressure monitoring and two-dimensional (2D) echocardiography were performed at basal time; then 30, 60, 120 and 180 min after infusion. The parameters measured were blood pressure (mmHg), systemic vascular resistance (SVR dynes center dot cm(5) center dot min(minus sign1)), pulmonary artery pressure (PAP mmHg), mean pulmonary capillary wedge pressure (PCWP mmHg) and cardiac index (CI 1 min/m(2)) using right heart catheterization and end-systolic volume (ESV ml) and end-diastolic volumes (EDV ml), ejection fraction (EF%) using 2D echocardiography. Placebo had no significant effects on any of the parameters (p = NS). Saterinone decreased SVR by 37% (p < 0.001), PAPm by 24% (p < 0.05), PCWP by 35% (p < 0.05), ESV by 27% (p < 0.01) and increased CI by 32% (p < 0.05) and EF by 45% (p < 0.05). Saterinone appears to be a potent drug that produces improvements in both cardiac hemodynamics and LV functional parameters. Further study with this interesting agent is indicated.
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PMID:Saterinone: A New Dual-Action Drug in the Acute Management of Chronic Heart Failure. 1186 96

We investigated the pulmonary vascular effects of prophylactic use of sildenafil, a specific phosphodiesterase-5 inhibitor, in late-gestation fetal lambs with chronic pulmonary hypertension. Fetal lambs were operated on at 129 +/- 1 days gestation (term = 147 days). Ductus arteriosus (DA) was compressed for 8 days to cause chronic pulmonary hypertension. Fetuses were treated with sildenafil (24 mg/day) or saline. Pulmonary vascular responses to increase in shear stress and in fetal PaO2 were studied at, respectively, day 4 and 6. Percent wall thickness of small pulmonary arteries (%WT) and the right ventricle-to-left ventricle plus septum ratio (RVH) were measured after completion of the study. In the control group, DA compression increased PA pressure (48 +/- 5 to 72 +/- 8 mmHg, P < 0.01) and pulmonary vascular resistance (PVR) (0.62 +/- 0.08 to 1.15 +/- 0.11 mmHg x ml(-1) x min(-1), P < 0.05). Similar increase in PAP was observed in the sildenafil group, but PVR did not change significantly (0.54 +/- 0.06 to 0.64 +/- 0.09 mmHg x ml(-1) x min(-1)). Acute DA compression, after brief decompression, elevated PVR 25% in controls and decreased PVR 35% in the sildenafil group. Increased fetal PaO2 did not change PVR in controls but decreased PVR 60% in the sildenafil group. %WT and RVH were not different between groups. Prophylactic sildenafil treatment prevents the rise in pulmonary vascular tone and altered vasoreactivity caused by DA compression in fetal lambs. These results support the hypothesis that elevated PDE5 activity is involved in the consequences of chronic pulmonary hypertension in the perinatal lung.
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PMID:Pulmonary vascular effects of sildenafil on the development of chronic pulmonary hypertension in the ovine fetus. 1568 94

In neonates with acute pulmonary hypertension (PHT), the dose-response effect of sildenafil citrate, a selective phosphodiesterase-5 inhibitor that can alleviate PHT, has not been detailedly examined. We tested the hypothesis that the treatment of hypoxia-induced acute PHT with sildenafil would dose-dependently reduce the elevated pulmonary and systemic arterial pressures (PAP and SAP, respectively) with no effect on the oxygenation in newborn animals. We also examined the regional hemodynamic responses. Using a randomized controlled design, piglets (age range, 1-3 days; weight range, 1.5-2.1 kg) were anesthetized and acutely instrumented to measure cardiac index, left common carotid, superior mesenteric and left renal arterial flow indexes, SAP, and PAP. After stabilization, hypoxia was induced with fractional inspired oxygen concentration at 0.15 and, subsequently, piglets were randomized to receive i.v. sildenafil at 0.06, 0.2, or 2.0 mg/kg per hour or normal saline (controls) for 90 min (n = 6 each). Within 30 min of hypoxia (PaO2, 31 +/- 5 mmHg), the piglets developed PHT (PAP, 33 +/- 5 vs. 26 +/- 4 mmHg at baseline; P < 0.05. Sildenafil dose-dependently reduced the hypoxia-induced PHT (PAP at 90 min: 33 +/- 6, 29 +/- 6, and 26 +/- 6 mmHg of 0.06, 0.2, and 2.0 mg/kg per hour, respectively, vs. 44 +/- 8 mmHg of controls; P < 0.05. Sildenafil at 2.0 mg/kg per hour had the greatest decrease in SAP (P < 0.05) with no significant change at 0.06 and 0.2 mg/kg per hour. Pulmonary selectivity (PAP:SAP ratio) was best in the group treated with 0.2 mg/kg per hour dosage of sildenafil (P < 0.05). There were no differences in cardiac index and regional flow indexes between groups. Although hypoxia decreased oxygen delivery and increased oxygen extraction with no significant effect on oxygen consumption, the administration of sildenafil did not affect the oxygen metabolism (vs. controls). In neonatal piglets, i.v. sildenafil dose-dependently alleviates the hypoxia-induced acute PHT, with the best pulmonary selectivity at 0.2 mg/kg per hour, and shows no significant effect on regional circulation and oxygen metabolism.
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PMID:Dose response of intravenous sildenafil on systemic and regional hemodynamics in hypoxic neonatal piglets. 1678 5

Pulmonary arterial hypertension (PAH) is commonly associated with CREST (Calcinosis, Raynaud phenomenon, Esophageal motility disorders, Sclerodactyly, and Telangiectasia) syndrome. Sildenafil, an oral phosphodiesterase type-5 inhibitor, may offer benefits in the pharmacological management of PAH. However, little is known about the long-term hemodynamic effects of sildenafil, and the potential role of sildenafil in long-term combination with beraprost, an oral prostacyclin analogue, remains unclear. We therefore examined the hemodynamic effect of oral sildenafil alone and when coadministered with beraprost in a patient with PAH associated with CREST syndrome. Traces of the acute hemodynamic effects of beraprost (20 microg) disappeared after 2 hours. In contrast, the acute hemodynamic effects of sildenafil (50 mg) produced a greater reduction in PAP (31%) and PVR (40%), and these effects also disappeared after 5 hours. After 1 month of combination therapy of sildenafil (25 mg) twice daily and beraprost (20 microg) 3 times daily, the fall in pulmonary artery pressure and pulmonary vascular resistance was sustained (31% in both). Furthermore, the patient had significantly improved her 3-minute walk test and NYHA function class without significant adverse effects at the reported doses. The findings indicate that oral sildenafil is a potent pulmonary vasodilator that appears to act synergistically with oral beraprost to cause sustained pulmonary vasodilatation in a patient with PAH associated with CREST syndrome.
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PMID:Combination therapy with oral sildenafil and beraprost for pulmonary arterial hypertension associated with CREST syndrome. 1759 7

Lipin 1 is a coregulator of DNA-bound transcription factors and a phosphatidic acid (PA) phosphatase (PAP) enzyme that catalyzes a critical step in the synthesis of glycerophospholipids. Lipin 1 is highly expressed in adipocytes, and constitutive loss of lipin 1 blocks adipocyte differentiation; however, the effects of Lpin1 deficiency in differentiated adipocytes are unknown. Here we report that adipocyte-specific Lpin1 gene recombination unexpectedly resulted in expression of a truncated lipin 1 protein lacking PAP activity but retaining transcriptional regulatory function. Loss of lipin 1-mediated PAP activity in adipocytes led to reduced glyceride synthesis and increased PA content. Characterization of the deficient mice also revealed that lipin 1 normally modulates cAMP-dependent signaling through protein kinase A to control lipolysis by metabolizing PA, which is an allosteric activator of phosphodiesterase 4 and the molecular target of rapamycin. Consistent with these findings, lipin 1 expression was significantly related to adipose tissue lipolytic rates and protein kinase A signaling in adipose tissue of obese human subjects. Taken together, our findings identify lipin 1 as a reciprocal regulator of triglyceride synthesis and hydrolysis in adipocytes, and suggest that regulation of lipolysis by lipin 1 is mediated by PA-dependent modulation of phosphodiesterase 4.
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PMID:Mice with an adipocyte-specific lipin 1 separation-of-function allele reveal unexpected roles for phosphatidic acid in metabolic regulation. 2326 81

Chronic hypoxia induces an increased production of nitric oxide (NO) in pulmonary prealveolar arterioles. Bioavailability of the NO in the pulmonary vessels correlates with concentration of L-arginine as well as activity of phosphodiesterase-5 enzyme (PDE-5). We tested a hypothesis whether a combination of L-arginine and PDE-5 inhibitor sildenafil has an additive effect in reduction of the hypoxic pulmonary hypertension (HPH) in rats. Animals were exposed to chronic normobaric hypoxia for 3 weeks. In the AH group, rats were administered L-arginine during chronic hypoxic exposure. In the SH group, rats were administered sildenafil during chronic hypoxic exposure. In the SAH group, rats were treated by the combination of L-arginine as well as sildenafil during exposure to chronic hypoxia. Mean PAP, structural remodeling of peripheral pulmonary arterioles (%DL) and RV/LV+S ratio was significantly decreased in the SAH group compared to hypoxic controls even decreased compared to the AH and the SH groups in first two measured parameters. Plasmatic concentration of cGMP and NOx were significantly lower in the SAH group compared to hypoxic controls. We demonstrate that NO synthase substrate L-arginine and phosphodiesterase-5 inhibitor sildenafil administered in combination are more potent in attenuation of the HPH compared to a treatment by substances given alone.
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PMID:L-arginine in combination with sildenafil potentiates the attenuation of hypoxic pulmonary hypertension in rats. 2386 84


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