Effects of phosphodiesterase inhibitor-induced insulin resistance on glucose and lipid metabolism in rats

AIM:To investigate the effects of milrinone (a selective phosphdiesterase III inhibitor PDE₃) on insulin secretion, blood glucose, plasma free fatty acids (FFA) and dose-response relationship, and assess possible effects of milrinone on glucose metabolism and insulin sensitivity in conscious rats.METHODS:The catheterized nonstressed rats were administered by the varying doses of milrinone (1, 5, 25 μmol/kg) and were compared with controls. A hyperinsulinaemic- euglycaemic clamp was established in awake rats, and milrinone(25 μmol/kg) and 25% dimethyl sulfoxide (DMSO, as a control) were given at 120 min during hyperinsulinaemic- euglycaemic clamp. Glucose turnover was decided by gas chromatograph mass spectrometer (GC-MS).RESULTS:After dosing, plasma FFA levels in 3 milrinone groups significantly increased compared with the controls and before dosing. The percentages of elevation of FFA by the different milrinone doses were very similar, 50%, 52%, 55% for 1, 5, 25 μmol/kg respectively at 2 min after dosing. Plasma insulin levels were significantly elevated in the 5 and 25 μmol/kg groups, and the effect of milrinone on glucose concentration was detectable only 25 μmol/kg group. During hyperinsulinaemic clamp, there were significant increase in plasma FFA (from 173.1±15.2 to 633.8±87.3 μEq/L) and hepatic glucose production (HGP), and a significant decrease in glucose infusion rates (GIR) (to about 21%).CONCLUSION:These data suggest that milrinone impaires the abilities of insulin to suppress lipolysis and HGP, and insulin-mediated glucose utilization in peripheral tissue. Therefore, milrinone administration may induce an acute insulin resistancein vivo.     

Interference with soil phosphatase activity by maize herbicidal treatment and incorporation of maize residues

Summary This study is concerned with the way alachlor, atrazine and metolachlor interfered with phosphatase activity in a clay loam soil unenriched and enriched with maize residues. Enrichment caused an increase in all phosphatase activities (acid and alkaline phosphomonoesterase, phosphodiesterase, phosphotriesterase) tested. Interference with phosphatase activity following herbicidal treatment was found in both unenriched and enriched soil samples. Statistically significant interference was dependent on soil enrichment, the type of herbicide and its rate of application and the time elapsed since the herbicidal treatment. The observed changes in phosphatase activities are attributed to herbicidal action on phosphatase-producing microorganisms. Among the herbicides tested, the acetanilide derivatives exerted a lesser inhibiting effect than atrazine. Nevertheless, all the altered phosphatase activities showed a tendency, more or less rapid, to reach the levels in the corresponding untreated soil samples.     

长期定位施肥对黑土磷酸酶活性的影响

对长期不同培肥制度下黑土磷酸酶活性进行研究。结果表明,中性磷酸单酯酶活性最高,磷酸二酯酶活性次之,磷酸三酯酶活性最低。不同施肥处理中性磷酸单酯酶活性顺序为:NPKNKM1+N2PK秸秆+N3PKCKM2+N1PK。磷酸二酯酶活性顺序为:M1+N2PKM2+N1PK秸秆+N3PKCKNKNPK。磷酸三酯酶活性各处理间无显著差异。     

Protection by cAMP and cGMP phosphodiesterase inhibitors of diazinon-induced hyperglycemia and oxidative/nitrosative stress in rat Langerhans islets cells: Molecular evidence for involvement of non-cholinergic mechanisms

The objective of this study was to study the effects of acute administration of diazinon alone or in combination with two phosphodiesterase (PDE) inhibitors with selectivity to cAMP and cGMP (theophylline and sildenafil, respectively) on oxidative/nitrosative stress biomarkers, including nitric oxide (NO), lipid peroxides (TBARS), total antioxidant power (TAP), and concentration of tumor necrosis factor (TNF-α) in isolated Langerhans islets, plasma glucose and insulin levels, and the activity of plasma cholinesterase (ChE). Examination by different doses of diazinon (15, 30, and 60 mg/kg) in single administration lead us to choose diazinon (30 mg/kg) in combination therapies. Theophylline and sildenafil were used at doses of 25 and 5 mg/kg, respectively. In all diazinon-treated groups, plasma ChE activity and plasma insulin level were significantly decreased and plasma glucose concentration and Langerhans islets TNF-α, TBARS, and NO levels were significantly increased in comparison to controls. The TAP did not change in comparison to control. In combination therapy, both theophylline and sildenafil restored diazinon-induced changes in plasma glucose concentration, Langerhans islets TNF-α, NO, and TBARS concentrations but Langerhans islets TAP, plasma insulin, and ChE levels. It is concluded that diazinon stimulates oxidative/nitrosative stress in Langerhans islets that results in hyperglycemia due to insufficiency of insulin. Altered glucagons/insulin ratio, activated hepatic glucose production/release, and insulin resistance are possible mechanisms. The protective effects of cAMP and cGMP PDE inhibitors in restoration of diazinon-induced oxidative/nitrosative stress and hyperglycemia stress back to their antioxidant potentials that seem to be independent of ChE inhibition.     

Comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled, blinded, and randomized study

BACKGROUND: Pimobendan (PIMO) is an inodilator that may have some beneficial effects in canine degenerative mitral valve disease (MVD). However, little information is available about its cardiac effects in dogs without systolic myocardial dysfunction. HYPOTHESIS: Compared to benazepril (BNZ), an angiotensin-converting enzyme inhibitor, PIMO may worsen valve regurgitation in early canine MVD. ANIMALS: Twelve Beagles with asymptomatic MVD were randomized into 2 groups (n = 6) receiving BNZ or PIMO at dosages of 0.25 mg/kg PO q24h and q12h respectively, for 512 days. METHODS: The study followed a blinded, randomized, prospective, and parallel group design. After day 512, the dogs were necropsied, and cardiac histopathology was performed in a blinded manner. RESULTS: A significant treatment effect was observed as soon as day 15 with increased systolic function in the PIMO group by comparison to baseline value as assessed by fractional shortening (P < .0001) and tissue Doppler variables (P = .001). Concurrently, the maximum area and peak velocity of the regurgitant jet signal increased (P < .001), whereas these variables remained stable in the BNZ group. Histologic grades of mitral valve lesions were more severe in the PIMO group than in the BNZ group. Moreover, acute focal hemorrhages, endothelial papillary hyperplasia, and infiltration of chordae tendinae with glycosaminoglycans were observed in the mitral valves of dogs from the PIMO group but not in those of the BNZ group. CONCLUSIONS AND CLINICAL IMPORTANCE: PIMO has adverse cardiac functional and morphologic effects in dogs with asymptomatic MVD. Additional investigation in dogs with symptomatic MVD is now warranted.     

木屑栽培香菇胞外纤维素酶和磷酸二酯酶的活性变化

不同木屑培养料栽培香菇菌丝生长盛期,原基形成期和子体成熟期胞外ＣＸ酶和Ｃ２酶的活性是逐渐增强的,以确保碳素营养的充分供应。不同木屑培养料的成分只影响酶活性的相对大小,而不影响酶活性的变化规律。纤维素酶活性对子实体形成不起决定作用。     

Advances in PDE5 inhibitors and diseases related to cGMP signaling pathway

Phosphodiesterase 5 （PDE5） inhibitors， as drugs to dilate the corpora cavernosa of the penis through sexual stimulation， are used to treat erectile dysfunction， and are also approved for treating pulmonary arterial hypertension. With the in-depth studies， PDE5 inhibitors have been approved to treat a variety of diseases， such as cardiovascular diseases， Alzheimer disease， etc， but there is currently no overall review on clinical applications of PDE5 inhibitors. As known， the classic pathway of PDE5 inhibitors promotes cyclic guanosine monophosphate （cGMP） production. However， reports on downstream pathways regulated by cGMP are still unclear. This review summarized the research and clinical application progress of PDE5 inhibitors in different diseases， and the pharmacological bases of PDE5 inhibitors through cGMP signaling pathway are discussed.     

Stability of hydrolytic enzyme activity and microbial phosphorus during storage of tropical rain forest soils

Storage can markedly influence microbial and biochemical properties in soils, yet recommendations for sample storage are based on studies of temperate soils that regularly experience extended cold periods. We assessed the influence of storage conditions on microbial phosphorus and the activity of four hydrolytic enzymes (phosphomonoesterase, phosphodiesterase, β-glucosidase, and N-acetyl-β-d-glucosaminidase) in three lowland tropical forest soils from the Republic of Panama that experience a constant warm temperature. The soils spanned a strong rainfall gradient and contained contrasting physical and chemical properties (pH 3.6-5.9; total carbon 26-50 g C kg⁻¹; clay 33-62%; total phosphorus 0.30-0.60 g P kg⁻¹). Storage treatments were: (i) room temperature (22 °C in the dark), (ii) refrigerated (4 °C in the dark), (iii) air-dried (10 d, 22 °C), and (iv) frozen (−35 °C). There were significant changes in enzyme activities and microbial phosphorus during refrigerated and room temperature storage, although changes were relatively small during the first two weeks. An initial marked decline in enzyme activities for one soil analyzed within 2 h of sampling was attributed to a flush of activity caused by sampling and soil preparation (sieving, etc.). For longer-term storage (>2 weeks), ambient laboratory temperature appeared preferable to freezing and cold storage, because one month of storage caused a marked decline in enzyme activities and microbial phosphorus in one soil. Freezing preserved the activities of some enzymes in some soils at rates comparable to cold or room temperature storage, but caused a marked decline in microbial phosphorus in two soils. Air-drying caused a marked decline in microbial phosphorus and the activity of all enzymes. We therefore conclude that enzyme assays and microbial phosphorus should be determined in tropical forest soils after no more than two weeks storage in the dark at ambient laboratory temperature.     

Assessing the bioavailability of dissolved organic phosphorus in pasture and cultivated soils treated with different rates of nitrogen fertiliser

A proportion of dissolved organic phosphorus (DOP) in soil leachates is readily available for uptake by aquatic organisms and, therefore, can represent a hazard to surface water quality. A study was conducted to characterise DOP in water extracts and soil P fractions of lysimeter soils (pasture before and after, and cultivated soil after leaching to simulate a wet winter-autumn) from a field trial. Data on DOP in drainage waters from the field trial were also generated. In water extracts, used as a surrogate for soil solution and drainage water, 70-90% of the total dissolved P (TDP) concentration was made up of DOP, of which 40% was hydrolysable by phosphatase enzymes. Proportions of hydrolysable DOP to TDP in drainage waters of the field trial were less than in water extracts due to enhanced DRP loss via dung inputs, but still large at 35% of DOP. Analysis of lysimeter soils by sequential fractionation indicated that several organic P fractions changed with land use and due to leaching. Further investigation using NaOH-EDTA extracts and ³¹P nuclear magnetic resonance spectroscopy indicated that the greatest changes were a decrease in the concentrations of orthophosphate diester P and an increase in orthophosphate monoester P. This was attributed to mineralization by cultivation and plant roots and also to the leaching of mobile diester P. This study suggests that in such soils with a dynamic soil organic P pool, the concentration of readily bioavailable P in soil solution and drainage waters and the potential to impair surface water quality cannot be determined from the DRP concentration alone.     

Phosphomonoesterase,phosphodiesterase, phosphotriesterase,and inorganic pyrophosphatase activities in forest soils in an alpine area: effect of pH on enzyme activity and extractability

We investigated different types of phosphatase activity (phosphomono-, phosphodi-, phosphotriesterase, inorganic pyrophosphatase) in five forest soils in Vorarlberg, Austria. Phosphatase activity was determined both in soils and in soil extracts prepared with different solutions (distilled water, 0.1M sodium pyrophosphate at pH 7, 0.1M sodium phosphate buffer/1M KCl at pH 6.5, and a modified universal buffer at pH 4, 6.5, 9, and 11). High phosphomonoesterase activity in these soils indicated a severe deficiency in available P. Acidic phosphomonoesterase prevailed over alkaline phosphomonoesterase activity. Phosphodiesterase was highest in the least acidic soil but no general trend towards an optimum pH was recognized. Phosphotriesterase activity was observed in only two of the five soils and favoured an alkaline optimum pH; this activity was not detected in strongly acid soils. Inorganic pyrophosphatase activity was high in soils with no phosphotriesterase. Phosphomonoesterase, phosphodiesterase and inorganic pyrophosphatase activities were much lower in soil extracts than in soils.