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)

Peripheral arterial disease affects approximately 8-10 million people in the United States. Approximately one-third to one-half of these individuals are symptomatic. The risk factors that contribute to peripheral arterial disease are similar to those associated with other forms of atherosclerosis, including diabetes mellitus, cigarette smoking, hypercholesterolemia, high blood pressure, and hyperhomocysteinemia. Of these, diabetes and cigarette smoking pose the greatest risk for developing peripheral arterial disease. The prognosis of patients with these risk factors is limited because of their greater risks for myocardial infarction, stroke, and cardiovascular death. Cardiovascular mortality correlates inversely with the ankle/brachial index, and the risk of death is greatest in those with the most severe peripheral arterial disease. Treatment regimens to reduce cardiovascular morbidity and mortality in patients with peripheral arterial disease should include risk factor modification and antiplatelet therapy. The cardinal symptoms of peripheral arterial disease include intermittent claudication and rest pain, with the latter being indicative of critical limb ischemia. Therapeutic strategies that focus on improving the patient's quality of life, reducing the severity of claudication, and improving limb viability include supervised exercise training, pharmacotherapy, and revascularization. Two drugs-pentoxifylline and cilostazol-currently are approved by the Food and Drug Administration for the treatment of patients with claudication. Meta-analyses have suggested that, compared with placebo, pentoxifylline improves maximal walking distance by approximately 20-25%. Cilostazol is a phosphodiesterase type 3 inhibitor. In clinical trials, cilostazol has consistently improved maximal walking distance as compared with placebo, with the range of improvement being approximately 40-60%. Drugs that are currently under investigation include propionyl-L-carnitine, vasodilator prostaglandins, L-arginine, and the angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factors.
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PMID:Medical management of peripheral arterial disease. 1140 4

Although intraportal infusion of adenosine suppressed the oxidative stress caused by activated neutrophils and attenuated ischemia-reperfusion injury of canine liver, high doses of adenosine elicit systemic hypotension. The present work demonstrates that combined use of low doses of adenosine and amrinone, a phosphodiesterase inhibitor, strongly inhibited reperfusion injury of the liver without eliciting hypotension. After 45 min ischemia followed by 60 min reperfusion of rat liver, low doses of adenosine and amrinone were administrated intraportally, resulting in significantly increased hepatic levels of cGMP, cAMP, nitrite plus nitrate in plasma, and decreased alanine aminotransferase in plasma without changing hemodynamics. Thus, intraportal administration of low doses of adenosine and amrinone increased the cyclic nucleotides, thereby improved microcirculation and attenuated reperfusion injury of the liver.
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PMID:Combined use of adenosine and amrinone inhibits reperfusion injury of rat liver. 1147 70

Disruption of any one of a large number of balanced systems that maintain cardiomyocyte structure and function can cause myocardial dysfunction. Such disruption can occur either in response to acute stresses such as cardiac surgery with cardiopulmonary bypass and cross-clamping of the aorta or because of more chronic stresses resulting from factors such as genetic abnormalities, infection, or chronic ischemia. Several currently available therapies such as beta-adrenergic receptor agonists and antagonists, phosphodiesterase inhibitors, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other agents affect cardiomyocytes in ways that are more far reaching than initially appreciated when these agents were first introduced into clinical practice. As our knowledge and understanding of myocardial dysfunction increases, particularly in the neonatal and pediatric patient, we will be able to further target interventions to highly specific perturbations of cellular function and individual genetic variability.
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PMID:Cellular and molecular aspects of myocardial dysfunction. 1159 64

Cardiac surgery with cardiopulmonary bypass (CPB) induces an acute phase reaction that has been implicated in the pathogenesis of several postoperative complications. Recent data indicate that a complex sequence of events leads to the final activation of leukocytes and endothelial cells (EC), which is responsible for cell dysfunction in different organs. Activation of the contact system, endotoxemia, ischemia and reperfusion injury and surgical trauma are all potential triggers of inflammation following CPB. Different pro- and anti-inflammatory mediators (cytokines, adhesion molecules) are involved and their release is mediated by intracellular transcription factors (nuclear factor-kappa B, NF-kappa B). In this review, we examine recent advances in the understanding of the pathophysiology of the CPB-induced acute phase reaction and evaluate the different pharmacological, technical and surgical strategies used to reduce its effects. Emphasis is given to the central role of transcription factor NF-kappa B in the complex mechanism of the inflammatory reaction and to the effects of compounds such as heparin and glycosaminoglycans, phosphodiesterase inhibitors and protease inhibitors whose role as anti-inflammatory agent has only recently been recognized.
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PMID:Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update. 1214 18

The inhibitory neuromodulator taurine is involved in osmoregulation and cell volume adjustments in the central nervous system. In addition, taurine protects neural cells from excitotoxicity and prevents harmful metabolic events evoked by cell-damaging conditions. The release of taurine in nervous cell preparations is greatly enhanced by glutamate receptor agonists and various cell-damaging conditions. NO-generating compounds also increase taurine release in the mouse hippocampus. The further involvement of the NO/cGMP pathway and protein kinases in preloaded [3H]taurine release from hippocampal slices from adult (3-month-old) and developing (7-day-old) mice in normoxia and in ischemia was now studied using a superfusion system. The release was enhanced by 8-Br-cGMP and the phosphodiesterase inhibitor 2-(2-propyloxyphenyl)-8-azapurin-6-one (zaprinast), particularly in the immature hippocampus, indicating that increased cGMP levels induce taurine release. The release was also increased by the inhibitor of soluble guanylyl cyclase, 1H-(1,2,4)oxadiazolo-(4,3a)quinoxalin-1-one (ODQ) and the protein kinase C activator 4beta-phorbol 12-myristate 13-acetate (PMA), but only in the adult hippocampus. The ischemia-induced release was also enhanced by increased cGMP levels in both adult and developing mice, whereas protein kinase inhibitors had no effects in any conditions. The results demonstrate that cGMP is able to modulate hippocampal taurine release in both adult and developing mice, the rise in cGMP levels evoking taurine release in normoxia and in ischemia. This could be part of the neuroprotective properties of taurine, being thus important particularly in cell-damaging conditions and in preventing excitotoxicity.
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PMID:Taurine release in the developing and adult mouse hippocampus: involvement of cyclic guanosine monophosphate. 1192 68

We report here studies on the regulation of the metabolism of adenosine 3',5'-monophosphate (cAMP) in established and primary cultures of rat pulmonary microvascular endothelial cells (RPMVEC). Inhibition by rolipram, a selective inhibitor of cAMP phosphodiesterase (PDE) of the PDE4 gene family, was required to achieve maximal cAMP accumulation induced by direct or receptor-mediated adenylate cyclase activation when measured by [3H]-adenine prelabeling. Rolipram increased cAMP accumulation more effectively than did forskolin, isoproterenol, or adenosine derivatives alone, although extensive synergy was seen with combined agents. High-affinity PDE4 inhibitors, but not low-affinity or non-selective inhibitors, were effective inducers of cAMP accumulation in intact cells. The maximum effects (i.e. intrinsic activities) of these agents in the intact cell did not correlate with their in vitro PDE4 inhibitory affinities. RPMVEC were shown to express almost exclusively the PDE4 gene family isoforms A6 and B3. Guanosine 3',5'-monophosphate hydrolysis, observed in other types of endothelial cells was not found in early or late passage RPMVEC. Reverse transcription-polymerase chain reaction identification of mRNAse supported these conclusions with the exception that PDE2 and PDE4D mRNA isoform transcripts were present. These studies also support the conclusion that the mechanism of rolipram reversal of rat lung ischemia-reperfusion-induced permeability involves PDE4 inhibition in the microvascular endothelial cells of the lung.
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PMID:Regulation of cyclic AMP in rat pulmonary microvascular endothelial cells by rolipram-sensitive cyclic AMP phosphodiesterase (PDE4). 1199 50

The effect of simulated ischemia [hypoxia, no glucose, extracellular pH (pH(o)) 6.4] on cGMP synthesis induced by stimulation of soluble (sGC) or particulate guanylyl cyclase (pGC) was investigated in adult rat cardiomyocytes. Intracellular cGMP content was measured after stimulation of sGC by S-nitroso-N-penicillamine (SNAP) or stimulation of pGC by natriuretic peptides [urodilatin (Uro), atrial natriuretic peptide (ANP), or C-type natriuretic peptide (CNP)] for 1 min in the presence of phosphodiesterase inhibitors. After 2 h of simulated ischemia, a decrease of >50% was observed in pGC-dependent cGMP synthesis, but no significant change was observed in sGC-dependent cGMP synthesis. The reduction in cGMP synthesis caused by simulated ischemia was mimicked by extracellular acidosis (pH(o) 6.4), which decreased pGC-mediated cGMP synthesis without altering sGC-mediated cGMP synthesis. An extreme sensitivity of pGC activity to low pH was also observed in membrane cell fractions. Hypoxia without acidosis (pH(o) 7.4) profoundly depressed cellular ATP content but did not change the response to SNAP, Uro, or ANP (selective agonists of pGC type A receptor). Only cGMP synthesis in response to CNP (a selective agonist of pGC type B receptor) was significantly reduced by ATP depletion. These data support the relevance of intracellular pH as a modulator of cGMP and suggest that, in ischemic cardiomyocytes, synthesis of cGMP would be mainly nitric oxide dependent.
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PMID:Effect of ischemia on soluble and particulate guanylyl cyclase-mediated cGMP synthesis in cardiomyocytes. 1258 38

Nonglycosidic inotropic agents have been used for the short-term management of low output states and hypotension complicating acute myocardial infarction for several years. Without adequate reperfusion of the ischemic myocardium, inotropic agents are seldom effective in producing sustained hemodynamic responses. Furthermore, the potential exists for enhancement of ischemia and extension of myocardial necrosis. Thus, inotropic and vasopressors therapy should be regarded as temporary supportive treatment in patients with acute coronary syndrome and should be discontinued as soon as feasible. Parenteral sympathomimetic agents, usually dobutamine, and phosphodiesterase inhibitors, usually milrinone, are used for the management of exacerbations of chronic systolic heart failure. Although hemodynamics, and occasionally clinical status, improve, such therapy is associated with increased mortality and can potentially hasten a patient's demise. Nonparenteral sympathomimetics, such as ibopamine, phosphodiesterase-III inhibitors, such as milrinone and enoximone, calcium-sensitizing agents, such as pimobendan, and other novel inotropic agents, such as vesnarinone, all increase mortality of patients with chronic heart failure. Furthermore, newer noninotropic agents, such as B-natriuretic peptide, have been introduced for treatment of decompensated heart failure. New nonpharmacologic devices, such as biventricular pacing, are available for the treatment of advanced heart failure. Thus, indications for the use of presently available nonglycosidic inotropic agents are limited and should be considered only for short-term therapy or when no other treatment is available.
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PMID:Role of nonglycosidic inotropic agents: indications, ethics, and limitations. 1269 31

In contradistinction to chronic critical limb ischemia, the peripheral arterial disease patient with intermittent claudication is at relatively low risk for limb loss. As a result, initial claudication management should employ non-interventional therapies rather than immediate catheter-based or surgical revascularization. Although exercise therapy is the most efficacious conservative treatment for claudication, supervised exercise programs are not widely available at present. Consequently, a pharmacologic agent can be utilized to lessen the symptoms and improve the function of the claudicant. This manuscript provides a comprehensive review of the various pharmacotherapies that have been investigated for improving walking distance in the setting of intermittent claudication. Cilostazol, a phosphodiesterase III inhibitor, appears to provide the greatest benefit, significantly improving not only walking distance but quality of life as well. Early trials indicate that propionyl-L-carnitine, oral prostaglandins, L-arginine, and therapeutic angiogenesis may eventually yield significant benefit in lessening the symptoms of intermittent claudication.
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PMID:Pharmacologic treatment for intermittent claudication. 1271 Aug 46

The effects of sildenafil (Viagra), a specific inhibitor of phosphodiesterase 5, on ischemic myocardium was examined using an isolated rat heart model. Rats were pretreated with sildenafil at doses ranging from 0.001 mg to 0.5 mg/kg body weight. After 60 min, isolated hearts were subjected to ischemia for 30 min followed by 2 h of reperfusion. The results demonstrated that at 0.05 mg/kg (and to some extent at 0.01 mg/kg), sildenafil provided significant cardioprotection as evidenced by improved ventricular recovery, a reduced incidence of ventricular fibrillation and decreased myocardial infarction. At higher doses, it caused a significant increase in the incidence of ventricular fibrillation while at very low doses it had no effect on cardiac function. As expected, sildenafil increased cyclic 3',5'-monophosphate (cGMP) content in the heart. The results demonstrate for the first time that within a narrow dose range, sildenafil can protect the heart from ischemia/reperfusion injury, probably through a cGMP-signaling pathway.
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PMID:Cardioprotection with sildenafil, a selective inhibitor of cyclic 3',5'-monophosphate-specific phosphodiesterase 5. 1277 74


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