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)

We examined the hypothesis that an increase in the myocardial cyclic adenosine monophosphate (cAMP) by a phosphodiesterase III inhibitor, E-1020, may ameliorate the hemodynamic and biochemical changes in rabbit hearts after cardioplegic arrest, and that this enzyme-mediated process is temperature-sensitive. Sixty-one male Japanese white rabbits weighing 2.8 to 3.5 kg were used. Isolated hearts were prepared for modified Langendorff circulation using modified Krebs-Henseleit bicarbonate solution bubbled with a 95% O2-5% CO2 gas mixture. Thirty or sixty minutes of cardioplegia at 37 degrees C, or thirty minutes of cardioplegia at 15 degrees C was followed by normothermic reperfusion for 60 minutes. E-1020, 0.1 mmol/L was added to the cardioplegic solution (Bretschneider's HTK solution). The left-ventricular function was measured with a latex balloon placed in the left-ventricular cavity. The myocardial cAMP was higher, the total myocardial calcium was lower in hearts with E-1020 than in hearts with HTK alone (p < 0.05). E-1020 at 0.1 mmol/L did increase the myocardial concentration of cAMP and the functional recovery, and prevented the increase in the myocardial total calcium. Temperature affected the myocardium to preserve myocardial concentrations of adenine nucleotide compounds and cAMP. Our results suggest that a 0.1 mmol/L E-1020 adjunct to HTK solution at 37 degrees C completely prevents left-ventricular functional depression during 30 min of cardioplegia induced with non-oxygenated HTK, but decreases its potential efficacy at 15 degrees C. The protective effects disappear if the ischemic period lasts 60 min at 37 degrees C.
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PMID:Effect of phosphodiesterase III-inhibitor (E-1020) adjunct to Bretschneider's HTK cardioplegic solution on myocardial preservation in rabbit heart. 889 57

1 In order to understand mechanisms that limit the safe ischaemic time of donor hearts, this study evaluated NO/cyclic GMP biosignalling in the recovery of function after cardioplegia and hypothermic storage. 2 Hearts removed from anaesthetized rats were either perfused in working mode (Fresh) or arrested (St. Thomas' II cardioplegia) and stored at 3 degrees C for 8 h (CPL) prior to working mode perfusion. LV work and indices of the production of NO (Ca2+-dependent and Ca2+-independent NOS), cyclic GMP (soluble guanylyl cyclase (sGC) and GTP) and superoxide (xanthine oxidase (XO) and xanthine dehydrogenase (XDH)) were measured. 3 Relative to Fresh hearts, CPL hearts were deficient in cyclic GMP and had poor function. Correction of cyclic GMP deficiency (SNP, 200 microM) improved LV work and LV compliance. SNP effects were prevented by inhibition of sGC (ODQ, 3 microM), and potentiated by inhibition of cyclic GMP-dependent phosphodiesterase (zaprinast, 20 microM). SNP (200 microM) had no effect on function of Fresh hearts. 4 NOS activities (pH = 7.2) were similar in CPL and Fresh hearts, but at end-ischaemic pH (6.3), Ca2+-dependent NOS activity was reduced. The sensitivity of sGC to SNP was greater, and activities of XO and XDH were higher, in CPL than in Fresh hearts. 5 The deficiency in NO biosignalling in CPL hearts may arise due to acidosis-induced inhibition of NOS activity, reduced availability of GTP and/or enhanced inactivation of NO by superoxide. These findings provide rationales for novel strategies to prevent the deficiency in NO biosignalling and so improve the function of the transplanted heart.
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PMID:Deficiency in myocardial NO biosignalling after cardioplegic arrest: mechanisms and contribution to post-storage mechanical dysfunction. 1055 23

We investigated whether permeability transition-mediated release of mitochondrial cytochrome c is a potential therapeutic target for treating acute spinal cord injury (SCI). Based on previous reports, minocycline, a second-generation tetracycline, exerts neuroprotection partially by inhibiting mitochondrial cytochrome c release and reactive microgliosis. We first evaluated cytochrome c release at the injury epicenter after a T10 contusive SCI in rats. Cytochrome c release peaked at approximately 4-8 h postinjury. A dose-response study generated a safe pharmacological regimen that enabled i.p. minocycline to significantly lower cytosolic cytochrome c at the epicenter 4 h after SCI. In the long-term study, i.p. minocycline (90 mg/kg administered 1 h after SCI followed by 45 mg/kg administered every 12 h for 5 days) markedly enhanced long-term hind limb locomotion relative to that of controls. Coordinated motor function and hind limb reflex recoveries also were improved significantly. Histopathology suggested that minocycline treatment alleviated later-phase tissue loss, with significant sparing of white matter and ventral horn motoneurons at levels adjacent to the epicenter. Furthermore, glial fibrillary acidic protein and 2',3' cyclic nucleotide 3' phosphodiesterase immunocytochemistry showed an evident reduction in astrogliosis and enhanced survival of oligodendrocytes. Therefore, release of mitochondrial cytochrome c is an important secondary injury mechanism in SCI. Drugs with multifaceted effects in antagonizing this process and microgliosis may protect a proportion of spinal cord tissue that is clinically significant for functional recovery. Minocycline, with its proven clinical safety, capability to cross the blood-brain barrier, and demonstrated efficacy during a clinically relevant therapeutic window, may become an effective therapy for acute SCI.
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PMID:Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. 1498 Dec 54

Central neurons regenerate axons if a permissive environment is provided; after spinal cord injury, however, inhibitory molecules are present that make the local environment nonpermissive. A promising new strategy for inducing neurons to overcome inhibitory signals is to activate cAMP signaling. Here we show that cAMP levels fall in the rostral spinal cord, sensorimotor cortex and brainstem after spinal cord contusion. Inhibition of cAMP hydrolysis by the phosphodiesterase IV inhibitor rolipram prevents this decrease and when combined with Schwann cell grafts promotes significant supraspinal and proprioceptive axon sparing and myelination. Furthermore, combining rolipram with an injection of db-cAMP near the graft not only prevents the drop in cAMP levels but increases them above those in uninjured controls. This further enhances axonal sparing and myelination, promotes growth of serotonergic fibers into and beyond grafts, and significantly improves locomotion. These findings show that cAMP levels are key for protection, growth and myelination of injured CNS axons in vivo and recovery of function.
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PMID:cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. 1515 4

Although there is no spontaneous regeneration of mammalian spinal axons after injury, they can be enticed to grow if cAMP is elevated in the neuronal cell bodies before the spinal axons are cut. Prophylactic injection of cAMP, however, is useless as therapy for spinal injuries. We now show that the phosphodiesterase 4 (PDE4) inhibitor rolipram (which readily crosses the blood-brain barrier) overcomes inhibitors of regeneration in myelin in culture and promotes regeneration in vivo. Two weeks after a hemisection lesion at C3/4, with embryonic spinal tissue implanted immediately at the lesion site, a 10-day delivery of rolipram results in considerable axon regrowth into the transplant and a significant improvement in motor function. Surprisingly, in rolipram-treated animals, there was also an attenuation of reactive gliosis. Hence, because rolipram promotes axon regeneration, attenuates the formation of the glial scar, and significantly enhances functional recovery, and because it is effective when delivered s.c., as well as post-injury, it is a strong candidate as a useful therapy subsequent to spinal cord injury.
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PMID:The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. 1517 85

In vitro, cAMP elevation alters neuronal responsiveness to diffusible growth factors and overcomes myelin-associated inhibitory molecules. Significant advances have been made recently in understanding the role of increases in cAMP in promoting axonal growth. Importantly, it has now been shown that cAMP elevation can promote axonal regeneration and functional recovery after central nervous system injury. Elevation of cAMP can be achieved via either direct application of cAMP analogs or an inhibitor of the enzyme phosphodiesterase that degrades cAMP in vivo. Current information points to a number of protein kinase A-mediated pathways (mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/akt pathway activation and Rho inactivation) underlying cAMP elevation-induced neuronal survival and axonal regeneration.
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PMID:Involvement of cAMP in neuronal survival and axonal regeneration. 1563 59

Numerous efforts have been made to maximize the efficacy of treatment for spinal cord injury (SCI). Recently, oligodendrocyte-type 2 astrocyte (O-2A) progenitor cells have been reported to remyelinate focal areas of demyelinated spinal cord in adult rats. We conducted a study to investigate the therapeutic potential of transplantation of O-2A cells in a rat model of acute SCI. SCI was induced with an NYU Impactor at T9 of rats. O-2A cells labeled with bromodeoxyuridine (BrdU) were transplanted into sites of SCI at 1 week after the induction of SCI. At 6 weeks after cell transplantation, a behavioral test showed significant functional improvement in animals that had received O-2A-cell transplants as compared to animals given cell-culture medium alone. An electrophysiological study revealed that the transplants did not improve the amplitude or latency of somatosensory evoked potentials, but a recording of motor evoked potentials showed that the latency of these potentials in the O-2A-cell-transplant group was significantly shorter than that in the group treated with cell-culture medium. Following transplantation of BrdU-labeled O-2A cells, cells positive for BrdU were detected at and near sites of SCI. Cells labeled for both BrdU and 2',3' -cyclic nucleotide-3-phosphodiesterase were also detected, showing that the transplanted O-2A cells differentiated into oligodendrocytes. By contrast, cells labeled for BrdU and glial fibrillary acidic protein, or for neuronal nuclei antigen, were not detected. Furthermore, a tract-tracing study showed that numbers of retrogradely labeled neurons increased in areas of the brain stem after O-2A-cell transplantation. The study data showed that after being transplanted into an animal with SCI, O-2A cells migrated to the area adjacent to the site of injury and differentiated into oligodendrocytes. The behavioral test and the electrophysiological and morphological studies showed that transplantation of O-2A cells may play an important role in functional recovery and the regeneration of axons after SCI.
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PMID:Effects of glial transplantation on functional recovery following acute spinal cord injury. 1589 2

Increasing age decreases the number of new neurons in the dentate gyrus and the subventricular zone (SVZ). Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, enhances neurogenesis in young rats. The present study tested the hypothesis that sildenafil augments neurogenesis in aged rats after focal cerebral ischemia. Nonischemic aged (18 months, n = 6) Wistar rats exhibited a significant reduction of actively proliferating and relatively quiescent cells in the SVZ measured by the number of minichromosome maintenance protein-2-positive (MCM-2+) cells, a marker of the proliferating cells, compared with nonischemic young (3-4 months, n = 8) rats. Occlusion of the middle cerebral artery did not increase the number of MCM-2+ cells in the SVZ of aged rats at 3 months after focal ischemia. However, treatment with sildenafil at a dose of 3 mg/kg (n = 8) daily for 7 consecutive days starting 7 days after focal ischemia significantly increased the number of MCM-2+ cells in the SVZ of aged rats compared with aged rats treated with saline (n = 8). Double immunostaining revealed that substantially more Ki67+ cells (a marker of proliferating cells) were doublecortin+ (a marker of migrating neuroblasts) in sildenafil-treated than in saline-treated aged animals. In addition, treatment with sildenafil significantly improved functional recovery compared with saline-treated rats. These data suggest that inhibition of PDE5 activity by sildenafil augments neurogenesis in the SVZ of aged ischemic rats, although these rats have reduced numbers of neural progenitor and stem cells in the SVZ.
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PMID:Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia. 1651 65

Sildenafil, a type 5 phosphodiesterase isoenzyme (PDE5) inhibitor with a short half-life, increases brain cyclic guanosine monophosphate (cGMP) levels and improves neurological functional recovery when administered after stroke. In the present study, we investigated the effects of tadalafil (Cialis), a long acting PDE5 inhibitor, on brain cGMP levels, neurogenesis, angiogenesis, and neurological function during stroke recovery in a rat model of embolic stroke. Male Wistar rats (n=28) were subjected to embolic middle cerebral artery (MCA) occlusion. Tadalafil was orally administered every 48 h at a dose of 2 mg/kg or 10 mg/kg for 6 consecutive days starting 24 h after stroke onset. Control animals received the equivalent volume of saline at the same time points. For mitotic labeling, bromodeoxyuridine (BrdU, 100 mg/kg) was administered twice a day at 5, 6, and 7 days after stroke. ELISA assays were performed to evaluate the specificity of the effect of tadalafil on cGMP. Treatment with tadalafil at a dose of 2 or 10 mg/kg significantly improved neurological functional recovery compared with saline-treated rats. In addition, tadalafil treatment increased cerebral vascular density and the percentage of BrdU-positive endothelial cells around the ischemic boundary compared with saline-treated rats. Moreover, tadalafil-treated rats showed greater ipsilateral SVZ cell proliferation than saline-treated rats. However, treatment with tadalafil did not reduce infarct volume when compared to the saline group. Tadalafil selectively increased cGMP but not cyclic adenosine monophosphate (cAMP) in brain. Our data demonstrate that treatment of ischemic stroke with tadalafil improved functional recovery, which was associated with increases of brain cGMP levels and enhancement of angiogenesis and neurogenesis.
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PMID:Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke. 1695 27

Ischemic preconditioning or phosphodiesterase inhibition improves lung protection during prolonged hypothermic storage. In ischemic preconditioning of cat lungs, adenosine A1 receptor antagonism was suggested as a possible mechanism. Some phosphodiesterase inhibitors (such as theophylline) are also adenosine antagonists; we showed theophylline to be particularly effective in protecting lungs. In isolated, perfused and ventilated rat lungs, we examined (1) whether synergy exists between phosphodiesterase inhibition and ischemic preconditioning and (2) whether theophylline acts both to inhibit phosphodiesterase and block adenosine receptors, by comparing its effects with enprofylline (selective phosphodiesterase inhibition) or xanthine amine congener (selective adenosine A1 receptor antagonism). In Study 1, rolipram (added to St Thomas' cardioplegia) or ischemic preconditioning before hypothermic storage (8 h) did not improve lung function during reperfusion (40 min); a combination of these treatments was also ineffective. In Study 2, lungs stored in St Thomas' cardioplegia containing enprofylline or theophylline had improved recovery of function compared to control lungs; however, xanthine amine congener was without effect. Thus, no interaction exists between phosphodiesterase inhibition and ischemic preconditioning. Adenosine A1 receptor antagonism plays no role in protecting rat lungs from the effects of prolonged hypothermic storage by either preconditioning or addition of theophylline to the storage solution.
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PMID:Long-term hypothermic lung preservation: does adenosine A1 receptor antagonism have a role in ischemic preconditioning protection? 1767 Feb 10


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