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)

To evaluate the effects of milrinone (MIL) on hemodynamics and lung water content, we used 10 mongrel dogs with pulmonary hypertension (PH). To induce pulmonary hypertension, we administered two injections of glass beads stirred in saline to dogs. Mean pulmonary arterial pressure (PAP) and pulmonary vascular resistance significantly increased following induction. Milrinone, which inhibits cyclic AMP phosphodiesterase-(PDE) demonstrated pulmonary vasodilation, indicated a reduction in these two parameters. To clarify the drug mechanism, we measured lung water content as extravascular lung thermal volume (ETVL) using a thermo/sodium double-indicator dilution method. The induction of pulmonary hypertension produced a transient reduction in extravascular lung thermal volume. The parameter remained constant following milrinone administration, whereas the control showed a gradual increase. Of the 10 dogs, five were killed to measure gravimetrically the volume of lung water content as a comparison with extravascular lung thermal volume. We concluded that milrinone produced pulmonary vasodilation which induced a reduction in the transmural capillary pressure gradient according to Starling's hypothesis. This study suggests that the reduction in the transmural pressure gradient induced by milrinone may also prevent the re-elevation in extravascular lung thermal volume. Milrinone increases the cyclic AMP level in the endothelium and in the platelet which may affect either directly or indirectly the permeability of capillary endothelium.
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PMID:Effects of milrinone on lung water content in dogs with acute pulmonary hypertension. 129 25

Enoximone, a phosphodiesterase inhibitor, has positive inotropic and vasodilating actions. To evaluate specific effects of this drug on the systemic and pulmonary vascular bed, we administered enoximone as a 10-minute intravenous bolus at two different doses of 2 and 3 mg/kg of body weight, at different days, to five Holstein calves with a Jarvik 7-70 ml total artificial heart (Symbion, Inc., Salt Lake City, Utah). The calves were monitored for aortic pressure, right atrial pressure, pulmonary arterial pressure, and left atrial pressure. For each experiment cardiac output was maintained constant, and systemic and pulmonary vascular resistances were calculated at 0, 15, 30, and 60 minutes and every hour for 8 hours after infusion. Statistical analysis used analysis of variance and the paired t test with Bonferroni's correction. Data showed the following: (1) a marked systemic vasodilating action of enoximone at peak effect at 30 minutes with a 20% decrease in systemic vascular resistance from baseline value under constant cardiac output, returning progressively to normal values throughout the 8 hours; (2) a comparable effect for the two separate doses tested; (3) no specific action on the pulmonary vascular bed with "nonunidirectional" changes in pulmonary vascular resistance. This model was validated by the infusion of prostaglandin I2 in the same animals, at different days, which significantly decreased pulmonary vascular resistance of 50% at peak effect, under constant cardiac output. In summary, enoximone showed a proper systemic vasodilating effect with no specific action on the pulmonary vascular bed in an animal model of the total artificial heart. Decrease in pulmonary vascular resistances obtained with enoximone in clinical practice seems more related to the inotropic properties of the drug. Enoximone should not be administered in pulmonary hypertension, as suggested before.
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PMID:Evaluation of direct effects of enoximone on systemic and pulmonary vascular bed in animals with a Jarvik total artificial heart. 153 41

Amrinone is the only phosphodiesterase fraction III inhibitor currently available in the USA for the treatment of perioperative biventricular failure. Patients with chronic congestive heart failure (CHF) show down-regulation of the beta 1-adrenergic receptor with a decrease in receptor density and altered responses to catecholamines. Intravenous administration of amrinone can transiently restore beta 1-adrenergic responses in patients who have CHF. Amrinone's mechanism of vasodilatation, independent of the beta 1-adrenergic receptor, nitrates, and calcium entry blockers, proves an important therapeutic option for pulmonary hypertension. The elimination half-life of amrinone in volunteers is 2.6-4.1 h, and 3.5 h when administered into the cardiopulmonary bypass (CPB) circuit. Different loading and infusion doses have been reported for amrinone. Investigators have demonstrated that increases in cardiac output following amrinone administration are directly related to plasma concentration. In cardiac surgical patients, following a dose of 0.75 mg kg-1 administered into the CPB circuit, plasma concentrations are subtherapeutic after 10 min. We believe that, when using amrinone to facilitate separation from CPB, a bolus dose of 1.5 mg kg-1 or more should be administered. If therapeutic levels need to be maintained in patients with biventricular failure, an infusion should also be administered after the bolus dose. Additive effects have been demonstrated when catecholamines are administered concomitantly with amrinone and other PDE III inhibitors to increase cyclic AMP in cardiac muscle and improve contractility. The use of amrinone with catecholamines is also important clinically, because together they attenuate the vasoconstrictive effects of catecholamines alone, while the catecholamines support perfusion pressure. Amrinone represents a novel drug for managing biventricular dysfunction in cardiac surgical patients.
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PMID:Perioperative experience with amrinone. 160 Sep 63

Pulmonary hypertension, systemic vasodilation and the supply dependency of oxygen uptake are the major problems associated with sepsis. Thus, the goal of haemodynamic therapy in septic patients is an increase in cardiac output large enough to permit adequate tissue oxygenation. The purpose of this study was to establish whether the additional use of the phosphodiesterase inhibitor amrinone is useful in hypodynamic septic patients with inadequate tissue perfusion. Nine patients who had developed the clinical signs of sepsis (temperature greater than 38.5 degrees C, leukocytosis greater than 15,000/mm3, thrombopenia less than 100,000/mm3 or a drop in platelet count greater than 30%, cardiovascular shock) were given amrinone 30 micrograms.kg-1.min-1 for one hour. All patients showed mixed venous oxygen saturations below 70% and oxygen extraction rates above 30%, despite maximum catecholamine therapy. Haemodynamic parameters were measured with the help of a pulmonary artery catheter. Statistical significance was checked using the Wilcoxon signed-ranks test. During amrinone application cardiac index increased significantly from 4.6.1.81.min-1.m-2 to 5.6 +/- 1.81.min-1.m-2 (p less than 0.01), while central venous pressure was kept constant by volume supply. Mean pulmonary artery pressure remained nearly unchanged, whereas mean arterial pressure dropped significantly from 91 +/- 13 mmHg to 75 +/- 8 mmHg (p less than 0.01). The oxygen supply rose during administration of amrinone by an average of 17%, which led to a rise in oxygen uptake. Independence of oxygen uptake from oxygen supply, however, could not be attained. In septic patients, amrinone increases cardiac output via pulmonary vasodilation. However, pronounced systemic vasodilation lowers arterial blood pressure, enhancing the risk of myocardial ischaemia.
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PMID:[Amrinone for cardiovascular therapy in hypodynamic septic patients?]. 161 30

There is increasing evidence that resting pulmonary vascular tone is mediated in part by the release of endothelium-derived relaxing factors (EDRF). Because L-arginine may be a precursor for EDRF synthesis, we studied the pulmonary vasodilating effects of L-arginine at rest and during pulmonary hypertension in 16 intact newborn lambs. At rest, the intravenous infusions of L-arginine (150 mg/kg) had no hemodynamic effects. However, during pulmonary hypertension induced by hypoxia or the infusion of U-46619 (a thromboxane A2 mimic), L-arginine decreased pulmonary arterial pressure by 22 and 27%, respectively (P less than 0.05). The decrease in pulmonary arterial pressure produced by L-arginine was blocked by methylene blue, a guanylate cyclase inhibitor, and augmented by Zapranast, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor (-17.9 vs. -31.2%, P less than 0.05). In addition, L-arginine partially reversed the pulmonary hypertension induced by N omega-nitro-L-arginine, a competitive EDRF synthesis inhibitor, but D-arginine had no hemodynamic effects. This study suggests that L-arginine produces pulmonary vasodilation by increasing cGMP concentrations, supporting the in vitro hypothesis that L-arginine is a precursor for EDRF synthesis, whose availability may become rate limiting during pulmonary hypertension.
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PMID:L-Arginine, a precursor of EDRF in vitro, produces pulmonary vasodilation in lambs. 165 28

The importance of right ventricular (RV) function in maintaining global cardiac performance is the focus of this discussion. The physiological determinants of normal right ventricular function will be discussed, with particular emphasis on the afterload and contractility characteristics of the right ventricle. Numerous clinical conditions have been shown to affect RV performance. These conditions include positive-pressure ventilation, ischemia, pulmonary hypertension, and cardiac surgery. Present methods for the perioperative evaluation of RV function include angiography, radionuclide techniques, thermodilution techniques, echocardiography, and magnetic resonance imaging. Traditional modalities for the treatment of RV dysfunction consist of pharmacological interventions (i.e., vasodilators and inotropes) and/or mechanical assist devices. Newer pharmacological strategies for the treatment of RV failure and associated pulmonary hypertension include the phosphodiesterase fraction III inhibitors and the prostaglandins, specifically PGE1. In summary, the accurate evaluation of perioperative RV performance combined with new treatment options will ensure maximal preservation of RV performance.
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PMID:Right ventricular function and failure: a review. 181 51

1. The limited therapeutic role of pulmonary vasodilation reflects lack of their selectivity for the pulmonary vasculature, and many drugs have been evaluated for effectiveness; however, none has gained widespread clinical use. 2. Milrinone (MIL) is a newly synthetized phosphodiesterase inhibitor, which has potent positive inotropic and vasodilatory effects. 3. The present study shows the effects of MIL on the pulmonary circulation in dogs with pulmonary hypertension due to autologous muscle-induced pulmonary embolism, and also demonstrates a comparison with those of dopamine and dobutamine. 4. As MIL showed potent vasodilatory effects on the pulmonary vasculature, it had a potential clinical role in the treatment of pulmonary hypertension.
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PMID:Vasodilatory effects of milrinone on pulmonary vasculature in dogs with pulmonary hypertension due to pulmonary embolism: a comparison with those of dopamine and dobutamine. 227 26

The pulmonary vasodilator effect of ZSY-27, a newly synthesized phosphodiesterase inhibitor, was studied in dogs with pulmonary hypertension resulting from autologous muscle-induced pulmonary embolism (PE). A bolus injection of ZSY-27 (1 mg/kg) significantly decreased mean pulmonary arterial pressure from 32 +/- 4 to 24 +/- 5 mm Hg and pulmonary vascular resistance index from 415 +/- 60 to 316 +/- 94 dyne.sec/cm5.m2. ZSY-27 did not change mean arterial pressure. The cardiac index was slightly increased and the systemic vascular resistance index was slightly decreased after ZSY-27 injection, but these changes were not statistically significant. This study suggests that ZSY-27 is a possible therapeutic agent for pulmonary hypertension secondary to PE.
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PMID:Selective pulmonary vasodilatory effect of ZSY-27 in dogs with pulmonary hypertension due to pulmonary embolism. 291 49

Acute hypoxia causes pulmonary hypertension in the fetus and newborn that is contrasted by systemic hypotension or normotension. To better understand the role of nitric oxide (NO) in this specific pulmonary vascular response, we determined the acute effects of decreased oxygenation on NO production in ovine fetal pulmonary and systemic (mesenteric) endothelial cells. NO was assessed by measuring cGMP accumulation in fetal vascular smooth muscle (VSM) cells during co-culture incubations of endothelium and VSM (40 s) in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Changes in cGMP were dependent on the endothelium and on NO synthase and guanylate cyclase activity. At high O2 (680 mm Hg), basal NO was detectable and NO increased 6- to 10-fold with bradykinin or A23187. In pulmonary endothelium, basal NO fell 58% at pO2 = 150 mm Hg and 51% at 40 mm Hg versus 680 mm Hg, while NO with bradykinin fell 56% and 63%, respectively. NO with A23187, however, was unchanged at 150 mm Hg, but it fell 56% at 40 mm Hg. In contrast, in systemic endothelium basal and stimulated NO production were not altered at lower O2. Findings were similar using pulmonary or systemic detector VSM cells, and exogenous L-arginine had no effect. Thus, decreased O2 acutely attenuates NO production specifically in fetal pulmonary endothelial cells. This process is not related to changes in O2 or L-arginine availability as substrates for NO synthase; alternatively, it may be partially mediated by specific effects of O2 on pulmonary endothelial cell calcium homeostasis.
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PMID:Oxygen modulates nitric oxide production selectively in fetal pulmonary endothelial cells. 752 86

We investigated the effect of zaprinast (M&B 22948), a specific cGMP phosphodiesterase inhibitor, on pulmonary arteries isolated from lambs with persistent pulmonary hypertension following prenatal ligation of the ductus arteriosus. Relaxations to sodium nitroprusside, which donates nitric oxide inside the smooth muscle cell, were significantly decreased in pulmonary arteries from ligated lambs. Pretreatment with 3 x 10(-5) M zaprinast restored them to levels close to those observed in untreated arteries from control animals. Further studies in intact newborn lambs were then conducted under three experimental conditions: (1) NO inhalation at 6 ppm, (2) zaprinast infusion at 0.05 mg/kg/min, and (3) combination therapy of zaprinast infusion in addition to inhaled NO at 6 ppm. Combined therapy with NO and zaprinast decreased the pulmonary artery pressure (34.3 +/- 3%) and pulmonary vascular resistance (64 +/- 7%) and increased pulmonary blood flow (88 +/- 34%) and postductal PaO2 (287 +/- 34%) to a significantly greater extent than NO alone, zaprinast alone, or the sum of these two responses, indicating a true synergistic effect. Zaprinast pretreatment also markedly increased the duration of pulmonary vasodilation to nitric oxide. There was no effect on systemic blood pressure with the combined therapy. We conclude that zaprinast pretreatment significantly enhances the effect of sodium nitroprusside on isolated pulmonary arteries, as well the effect of inhaled NO at 6 ppm in newborn lambs with persistent pulmonary hypertension. We speculate that phosphodiesterase inhibition may increase the response rate to NO or allow the use of much lower inhaled concentrations of NO.
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PMID:The cGMP phosphodiesterase inhibitor zaprinast enhances the effect of nitric oxide. 758 2


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