Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to determine, in an animal model, the effects of tadalafil on myocardial infarct size (IS), hemodynamics and regional myocardial blood flow after myocardial ischemia and reperfusion. Patients with erectile dysfunction (ED) often have risk factors for coronary artery disease. Tadalafil, a long-acting inhibitor of the enzyme phosphodiesterase-5 (PDE5), is used for the treatment of ED; there are no previous data regarding tadalafil in the setting of coronary artery occlusion (CAO). Sprague-Dawley male rats were treated with tadalafil or vehicle (10 mg/kg, by gastric gavage), 2 h before a 30 min CAO. Heart rate was comparable between tadalafil and control groups. Tadalafil reduced mean arterial pressure (P=0.009), systolic (P=0.035) and diastolic (P=0.009) blood pressures during ischemia/reperfusion. Tadalafil significantly reduced IS (42+/-2%) versus controls (54+/-3%) (P=0.006). For the first time, we showed that the PDE5 inhibitor, tadalafil, was well tolerated and cardioprotective in the setting of an experimental myocardial infarction, by substantially reducing ischemic cell death.
 ...
PMID:The phosphodiesterase-5 inhibitor tadalafil reduces myocardial infarct size. 1713 1

GABA is the inhibitory neurotransmitter in most brain stem nuclei. The properties of release of preloaded [(3)H]GABA were now investigated with slices from the mouse brain stem under normal and ischemic (oxygen and glucose deprivation) conditions, using a superfusion system. The ischemic GABA release increased about fourfold in comparison with normal conditions. The tyrosine kinase inhibitor genistein had no effect on GABA release, while the phospholipase inhibitor quinacrine reduced both the basal and K(+)-evoked release in normoxia and ischemia. The activator of protein kinase C (PKC) 4beta-phorbol 12-myristate 13-acetate had no effects on the releases, whereas the PKC inhibitor chelerythrine reduced the basal release in ischemia. When the cyclic guanosine monophosphate (cGMP) levels were increased by superfusion with zaprinast and other phosphodiesterase inhibitors, GABA release was reduced under normal conditions. The NO donors S-nitroso-N-acetylpenicillamine (SNAP) and hydroxylamine (HA) enhanced the basal and K(+)-stimulated release by acting directly on presynaptic terminals. Under ischemic conditions GABA release was enhanced when cGMP levels were increased by zaprinast. This effect was confirmed by inhibition of the release by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The NO-producing agents SNAP, HA, and sodium nitroprusside potentiated GABA release in ischemia. These effects were reduced by the NO synthase inhibitor N(G)-nitro-L: -arginine, but not by ODQ. The results show that particularly NO and cGMP regulate both normal and ischemic GABA release in the brain stem. Their effects are however complex.
 ...
PMID:Modulation of GABA release by second messenger substances and NO in mouse brain stem slices under normal and ischemic conditions. 1705 71

Excessive activation of the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) plays a prominent role in various of models of cellular injury. Here, we identify poly(ADP-ribose) (PAR) polymer, a product of PARP-1 activity, as a previously uncharacterized cell death signal. PAR polymer is directly toxic to neurons, and degradation of PAR polymer by poly(ADP-ribose) glycohydrolase (PARG) or phosphodiesterase 1 prevents PAR polymer-induced cell death. PARP-1-dependent, NMDA excitotoxicity of cortical neurons is reduced by neutralizing antibodies to PAR and by overexpression of PARG. Neuronal cultures with reduced levels of PARG are more sensitive to NMDA excitotoxicity than WT cultures. Transgenic mice overexpressing PARG have significantly reduced infarct volumes after focal ischemia. Conversely, mice with reduced levels of PARG have significantly increased infarct volumes after focal ischemia compared with WT littermate controls. These results reveal PAR polymer as a signaling molecule that induces cell death and suggests that interference with PAR polymer signaling may offer innovative therapeutic approaches for the treatment of cellular injury.
 ...
PMID:Poly(ADP-ribose) (PAR) polymer is a death signal. 1711 82

Levosimendan is a calcium sensitizer that is currently in the focus of intensive care medicine because it may be superior to standard inotropic agents in the treatment of acute myocardial insufficiency. The effects of levosimendan mainly depend on three predominant mechanisms: 1) positive inotropic effect by increasing the sensitivity of cardiac myofilaments to calcium ions, 2) vasodilatory effect by stimulation of adenosine triphosphate-sensitive potassium channels and 3) inhibition of phosphodiesterase-III. In a large number of experimental and clinical studies further possible indications for levosimendan have been described, e.g. cardioprotection during ischemia, cardiogenic shock, septic myocardial insufficiency and pulmonary hypertension. This review article critically summarizes the current scientific and clinical knowledge about levosimendan, its pharmacologic characteristics, mechanisms of action as well as indications and potential risks.
 ...
PMID:[Role of Levosimendan in intensive care treatment of myocardial insufficiency]. 1713 Nov 37

Cilostazol, a selective inhibitor of phosphodiesterase 3, exerts neuroprotective effects on acute brain injury after cerebral ischemia in rats. However, it is unknown whether cilostazol affects the subacute or chronic ischemic injury. In the present study, we evaluated the dose- and time-dependent effects of cilostazol on acute ischemic brain injury and the long-lasting effect on the late (subacute/chronic) injury in mice with focal cerebral ischemia induced by transient middle cerebral artery occlusion. We found that pre-treatment of cilostazol (injected i.p. at 30 min before ischemia) significantly ameliorated the acute injury 24 h after ischemia, and the effective doses were 3-10 mg/kg. The post-treatment of cilostazol (10 mg/kg) was effective on the acute injury when it was injected 1 and 2 h after ischemia. In addition, for the late injury, post-treatment of cilostazol (10 mg/kg, i.p., for 7 consecutive days after ischemia) attenuated neurological dysfunctions, brain atrophy and infarct volume. It also inhibited astrocyte proliferation/glial scar formation and accelerated the angiogenesis in the ischemic boundary zone 7 and 28 days after ischemia. Thus, we conclude that cilostazol protects against not only the acute injury, but also the late injury in mice with focal cerebral ischemia; especially it can modify brain remodeling, astrogliosis and angiogenesis.
 ...
PMID:Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic brain injuries. 1716 38

Myocardial ischemia-reperfusion injury occurs in a wide spectrum of patients, ranging from survivors of out-of-hospital cardiac arrest to acute myocardial infarction victims as well as patients undergoing cardiac surgery, and represents a major public health burden. This injury contributes significantly to morbidity and mortality, despite meticulous adherence to presently known principles of myocardial protection. Despite the considerable progress that has been made in the field of myocardial protection, high-risk subsets of patients continue to exhibit ischemia-reperfusion-related complications, including prolonged contractile dysfunction (stunning), low-output syndrome, perioperative myocardial infarction, and cardiac failure, requiring prolonged intensive care. Sildenafil, a phosphodiesterase 5 inhibitor, currently licensed for the treatment of erectile dysfunction and pulmonary hypertension has shown great promise in animal studies as a possible pharmacologic agent for cardioprotection. This review article discusses the pharmacology of sildenafil and focuses on the available evidence from animal studies on the potential role of sildenafil for treating ischemia-reperfusion injury with its implications for clinical practice.
 ...
PMID:Cardioprotection with sildenafil: implications for clinical practice. 1716 4

During the past 18 years, sildenafil has evolved from a potential anti-angina drug to an on-demand treatment for erectile dysfunction and more recently to a new orally active treatment for pulmonary hypertension. Recent studies suggest that the drug has powerful cardioprotective effect against ischemia/reperfusion injury, doxorubicin-induced cardiomyopathy and anti-hypertensive effect induced by chronic inhibition of nitric oxide synthase in animals. Based on several recent basic and clinical studies, it is clear that sildenafil and other clinically approved type-5 phosphodiesterase-5 inhibitors including vardenafil and tadalafil will eventually be developed for several cardiovascular indications including essential hypertension, endothelial dysfunction, ischemia/reperfusion injury, myocardial infarction, ventricular remodeling and heart failure.
 ...
PMID:Cardiovascular protection with sildenafil following chronic inhibition of nitric oxide synthase. 1724 65

Serine/threonine protein phosphatase 1 (PP1) regulates multiple cellular processes. Protein phosphorylation-dephosphorylation is largely altered during ischemia and subsequent reperfusion. The brain is particularly vulnerable to stress resulting from ischemia-reperfusion (IR), however, the acquisition of ischemic tolerance (IT) protects against IR stress. We studied PP1 complexes in response to IR stress and IT in brain using proteomic characterization of PP1 complexes in animal models of IR and IT. PP1alpha and PP1gamma were immunoprecipitated and resolved by 2-D. DIGE analysis detected 14 different PP1-interacting proteins that exhibited significant changes in their association with PP1alpha or PP1gamma. These proteins were identified by MALDI-TOF MS. Seven had the PP1-binding RVxF motif. IR altered the interaction of heat shock cognate 71 kDa-protein, creatine kinase B, and dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP32) with both PP1alpha and PP1gamma, and the interaction of phosphodiesterase-6B, transitional ER ATPase, lamin-A, glucose-regulated 78 kDa-protein, dihydropyrimidinase-related protein-2, gamma-enolase, neurofilament-L, and ubiquitin ligase SIAH2 with PP1gamma. IT prevented most of the IR-induced effects. This study identifies novel PP1alpha- and PP1gamma-interacting proteins and reveals an in vivo modularity of PP1 holoenzymes in response to physiological ischemic stress. It supports a potential role of PP1 in IR stress and as a target of the endogenous protective mechanisms induced by IT.
 ...
PMID:Proteomic characterization of protein phosphatase 1 complexes in ischemia-reperfusion and ischemic tolerance. 1768 50

Despite the proven clinical efficacy of phosphodiesterase inhibitors in the treatment of erectile dysfunction (ED), some patients do not respond to the medication. By means of nailfold capillary microscopy in patients with concomitant coronary artery disease (CAD) and ED, it was evaluated whether the extent of microvascular dysregulation predicts the responsiveness to tadalafil (TAD) in terms of erectile function. The ED of each patient was assessed by the International Index of Erectile Function (IIEF). Patients presenting both, documented CAD and ED, showed a significantly reduced capillary red blood cell velocity (v(RBC)) at rest and after 3 min of ischemia compared with age-matched controls. At 2 h after intake of 20 mg of TAD, a significant increase of v(RBC) at rest as well as during postischemic hyperemia was found. Patients who reported no improvement of their ED after the use of TAD demonstrated no changes in the duration of postischemic (DpH) hyperemia, or even a reduction of the DpH. The majority of the patients, who reported at least one successful sexual intercourse due to TAD, had a prolongation of DpH. We conclude that assessment of microvascular regulation by nailfold capillary microscopy can predict the probability of a treatment failure with phosphodiesterase inhibitors in patients with ED. Moreover, as endothelial dysfunction is the common underlying pathophysiological process of ED and cardiovascular diseases, the test may help to identify patients at risk for the development of atherosclerosis and following cardiovascular events.
 ...
PMID:Cutaneous microcirculatory function predicts the responsiveness to tadalafil in patients with erectile dysfunction and coronary artery disease. 1770 23

An endovascular treatment of vasospasm following a subarachnoid aneurysmal haemorrhage is to be implemented if the patient presents clinical or biological symptoms arguing for brain ischemia in conjunction with increased Doppler velocities despite well controlled systemic haemodynamic. Treatment might be either pharmacological or haemodynamic. Calcium and phosphodiesterase inhibitors can be administered. The former could also provide a neuroprotective effect as compared to the latter. In Europe, nimodipine is widely used whereas nicardipine and verapamil are the major molecules administered in North America where iv nimodipine is not FDA approved. Papaverine is less used nowadays because of its short duration of action and of the risk of aggravation of raised intracranial pressure. Balloon angioplasty has a long lasting effect but can be applied only to proximal spasm. Complications of its use are rare but life threatening. In some cases, both the pharmacological approach and the mechanical approach are used in combination.
 ...
PMID:[Endovascular treatment of vasospasm following subarachnoid aneurysmal haemorrhage]. 1793 40


<< Previous 1 2 3 4 5 6 7 8 9 10