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)

Ovarian function may be modulated by cells of the immune system. We have investigated the role of neutrophils (polymorphonuclear leukocytes) on rat luteal cell function. Activated neutrophils inhibited LH-sensitive cAMP accumulation, which was dependent on neutrophil cell number. At a concentration of 10(6) neutrophils/ml and 10(5) luteal cells/ml, LH-stimulated cAMP accumulation was inhibited by 50%. The inhibitory effect of activated neutrophils was reversed by superoxide dismutase (SOD) and catalase. LH-stimulated progesterone production was also inhibited by activated neutrophils. Progesterone production by 10(5) luteal cells was inhibited approximately 20% in the presence of 10(6) activated neutrophils, and this inhibition was blocked by SOD and catalase. Conditioned medium from activated neutrophils also produced inhibitory effects on LH-stimulated cAMP accumulation and progesterone production, which could be reversed by SOD and catalase. The phosphodiesterase inhibitor isobutylmethylxanthine had no significant effect on the inhibition of cAMP accumulation by conditioned medium from activated neutrophils. Luteal cells loaded with a fluorescent indicator for determining intracellular reactive oxygen species (dichlorofluorescein diacetate) showed increased fluorescence in the presence of activated neutrophils. No increase in fluorescence occurred in the absence of neutrophils or in the presence of SOD and catalase. These studies demonstrate that reactive oxygen species produced by activated neutrophils can enter the luteal cell and cause antigonadotropic effects. Although the experimental model used in the present studies may not be truly physiological, the data demonstrate that neutrophils may play a role in functional and structural regression of the corpus luteum in the rat.
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PMID:Effects of neutrophils in rat luteal cells. 131 Feb 72

Alterations in endothelium-derived relaxing factor (EDRF) production or mechanism of action may be involved in the responses of the developing pulmonary vasculature to changes in oxygenation. In this study the effects of acute changes in in vitro oxygen tension on EDRF production were determined in isolated segments of ovine fetal intrapulmonary arteries (4th generation) obtained at 125-135 days of gestation (term 144 +/- 4 days). EDRF production was assessed by measuring segment guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in the presence of a phosphodiesterase inhibitor. Basal (nonstimulated) cGMP production and cGMP production with acetylcholine (ACh) stimulation were dependent on the presence of the endothelium, on the availability of L-arginine, and on soluble guanylate cyclase activity, confirming that they were indicative of EDRF production. cGMP production with sodium nitroprusside (SNP) was used to discriminate changes in the sensitivity of soluble guanylate cyclase with varying conditions. With decreasing oxygen tension, basal and ACh-stimulated cGMP production were attenuated, whereas cGMP production with SNP was not, indicating oxygen modulation of EDRF production. Studies of endothelium-dependent relaxation yielded comparable findings in that the response to ACh was attenuated, but that to SNP was not altered by decreased oxygenation. In addition, the decline in endothelium-dependent relaxation with decreased oxygen tension was rapidly reversed when oxygenation was increased. Parallel experiments examining cGMP production in similarly sized mesenteric arteries revealed that the effect of oxygen on pulmonary artery EDRF production may be specific to that vascular bed. These findings indicate that oxygen selectively modulates EDRF production and endothelium-dependent relaxation in ovine fetal pulmonary arteries. Direct effects of oxygen on EDRF production may at least partially underlie the responses of the developing pulmonary circulation to changes in oxygenation.
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PMID:Oxygen modulates endothelium-derived relaxing factor production in fetal pulmonary arteries. 131 28

1. In right ventricular papillary muscles from control ferrets, flosequinan (10(-7)-10(-4) M) produced a concentration-dependent positive inotropic effect (10(-5) M = 153 +/- 24, 10(-4) M = 198 +/- 44% increase in isometric tension; control tension = 100%; n = 11) associated with a corresponding increase in amplitude of the intracellular Ca2+ ([Ca2+]i) transient recorded with aequorin (10(-5) M = 133 +/- 11, 10(-4) M = 187 +/- 36% increase in [Ca2+]i transient; n = 11). 2. The positive inotropic effect of flosequinan in control ferret ventricular muscle was neither blocked by propranolol (6 x 10(-7) M), nor associated with the abbreviation of the [Ca2+]i transient and contraction that is typical of catecholamines. 3. Neither flosequinan (n = 12) nor BTS 53 554, its sulphone metabolite (n = 6) produced a positive inotropic effect or altered the time course of contraction in myocardium from the hearts of patients with end-stage failure. 4. In contrast to milrinone, which produces a positive inotropic effect via phosphodiesterase inhibition, the unresponsiveness of myopathic human myocardium to flosequinan was not restored after intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were increased by prior treatment with forskolin (n = 13). 5. Taken together, these data indicate that flosequinan has a direct positive inotropic effect that is Ca(2+)-dependent, but independent of changes in intracellular cyclic AMP concentrations. 6. The positive inotropic effect may be species-dependent or altered by the presence of hypertrophy and/or heart failure. However, when used therapeutically in patients with severe heart failure, our data suggest that flosequinan should not adversely affect myocardial oxygen consumption through direct or catecholamine-mediated actions on the heart.
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PMID:Differential inotropic effects of flosequinan in ventricular muscle from normal ferrets versus patients with end-stage heart failure. 132 72

The cardiovascular effects of NKH477 (6-(3-dimethylaminopropionyl)forskolin hydrochloride), a novel water-soluble forskolin derivative, were investigated in dogs. Intravenous (i.v.) injections of NKH477 (1-30 micrograms/kg) caused dose-related increases in left ventricular dP/dtmax (LVdP/dtmax), coronary and femoral artery blood flow (CBF, FBF), heart rate (HR), and myocardial oxygen consumption (MVO2) and a dose-related decrease in blood pressure (BP) in anesthetized dogs. The regression analysis between CBF and MVO2 showed that NKH477 did not influence substantially the balance of oxygen supply and demand. Infusions of NKH477 (0.15-0.6 microgram/kg/min i.v.) also increased LVdP/dtmax, cardiac output (CO), and HR and decreased BP, pulmonary arterial diastolic pressure, and total peripheral resistance (TPR) in a dose-dependent manner. In contrast to forskolin, NKH477 administered intraduodenally (0.05-0.2 mg/kg) and orally (0.15 and 0.3 mg/kg) clearly exhibited cardiovascular actions, as it did in i.v. administration, indicating that NKH477 is orally active. No arrhythmias were induced by NKH477 in any study. NKH477, like forskolin, showed adenylate cyclase stimulant activity in guinea pig ventricular membrane but did not inhibit Na+, K(+)-ATPase or phosphodiesterase (PDE) activity. Thus, NKH477 can be characterized as a potent, orally active, water-soluble forskolin derivative, which suggests that NKH477 is a useful inodilator for treatment of heart failure, especially in the severe stage with beta-adrenoceptor downregulation.
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PMID:Cardiovascular and adenylate cyclase stimulant properties of NKH477, a novel water-soluble forskolin derivative. 138 Jun 7

After cardiopulmonary bypass (CPB), some patients may require circulatory support. This study examined the role of the phosphodiesterase-III inhibitor, enoximone, in cardiac surgery. Eighty patients selected by chance were allocated randomly to two groups: 40 patients received enoximone 1.0 mg kg-1 approximately 10 min before weaning from CPB and 40 served as a control group. Additional pharmacological therapy (adrenaline, noradrenaline, nitroglycerin) was given, when necessary, by anaesthetists who were not involved in the study. In addition to standard monitoring, skin capillary blood flow was assessed using a laser Doppler technique before, during and after CPB until 2 h after the end of the operation. In the period after bypass, cardiac index was always significantly greater in the enoximone than in the control group. Systemic and pulmonary vascular resistance were less in the enoximone-treated patients, indicating a reduction in right and left ventricular wall stress. Oxygen consumption in the enoximone patients was significantly greater after CPB, whereas intrapulmonary shunting was comparable in the two groups. In comparison with baseline values, skin capillary blood flow in the enoximone patients was always greater than that in the control group. In comparison with the control patients, significantly fewer enoximone patients needed adrenaline, and in a smaller dose, even 2 h after operation, whereas more enoximone patients required noradrenaline therapy for a short period. We conclude that the use of enoximone before weaning from CPB improved overall cardiac function, reduced the need of catecholaminergic inotropic support, and provided increased organ perfusion up to 2 h after operation.
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PMID:The role of enoximone in cardiac surgery. 3286 4

Endotoxin is a major mediator of the life-threatening cardiovascular dysfunction that characterizes Gram-negative sepsis. In animal models of endotoxemia, pretreatment with ibuprofen or pentoxifylline attenuates some of these cardiovascular changes. To evaluate the effects of these agents on the human cardiovascular response to endotoxemia, hemodynamic variables were measured serially in 24 normal subjects who were given intravenous endotoxin. The subjects were randomized to receive oral ibuprofen (n = 9), pentoxifylline (n = 10), or no medication before endotoxin administration (n = 5). The subjects were volume loaded 3-5 h after endotoxin administration, and hemodynamic measurements were reassessed. Core temperature after endotoxin alone or endotoxin-pentoxifylline approached a maximum at 3 h (greater than or equal to 38.6 degrees C), while the endotoxin-ibuprofen group remained afebrile. At 3 and 5 h, all three groups had significant increases in heart rate, cardiac index, oxygen delivery, and oxygen consumption, while systemic vascular resistance index decreased significantly from baseline. The oxygen extraction ratio remained unchanged. After volume loading, the left ventricular ejection fraction and left ventricular end-diastolic and end-systolic volume indexes did not differ among the groups. The hyperdynamic cardiovascular response to endotoxin in humans occurs in the absence of fever and is not significantly ameliorated by oral cyclooxygenase or phosphodiesterase inhibition.
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PMID:Effects of ibuprofen and pentoxifylline on the cardiovascular response of normal humans to endotoxin. 140 57

Indolidan (IN) experimentally inhibits type IV phosphodiesterase. It was administered to twelve patients (age 64 +/- 15 years) with New York Heart Association (NYHA) class 2-3 congestive heart failure in which digoxin and diuretic therapy were continued. IN was administered i.v. at 1,180 +/- 340 micrograms (15 micrograms/kg) over two hours. After 24 hours, IN was given p.o. at 231 +/- 44 micrograms. The time course effect of IN i.v. revealed an increase in cardiac index and a decrease in pulmonary capillary wedge pressure and blood pressure. Daily oral administration of IN or placebo was carried out for up to 3 months. There were no significant hemodynamic changes of chronically administered IN. The maximum oxygen uptake increased in placebo relative to IN therapy. IN tended to be arrhythmogenic as evidenced by a general increased frequency of ventricular premature contractions of both single and paired type. Therefore, IN had some hemodynamic efficacy on acute i.v. and p.o. administration but not during chronic therapy, and there was negative safety features of arrhythmias.
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PMID:Clinical effect of indolidan in congestive heart failure. 144 58

If the failing left ventricle could be given an effective push, other approaches to the treatment of heart failure would not be needed. We have inotropes only for short-term parenteral use. We have no safe inotrope for chronic oral use. The effect of digitalis is only feeble and the phosphodiesterase inhibitors seem to increase mortality from sudden death. Diuretics are dramatic for acute pulmonary oedema and the mainstay for chronic fluid retention but do not improve the pump and by reducing blood volume stimulate the renin angiotensin system to vasoconstriction, further fluid retention and hypokalaemia. Nitrates drop pre-load without reducing blood volume but tolerance is a problem and stroke volume does not increase. Reduction of afterload helps the failing ventricle to empty, the pull and output increases. The angiotensin converting enzyme inhibitors (ACEI) are now the cornerstone of heart failure treatment, reducing mortality in severe heart failure (CONSENSUS) and superior to standard vasodilator therapy (V-HeFT-2) at improving the survival of patients with mild to moderate heart failure. ACEI can reduce the incidence of ventricular ectopy and probably do this through improving left ventricular function, from decreasing sympathetic tone, reducing myocardial oxygen demand or increasing serum potassium but ACEI did not diminish the incidence of sudden death in the SOLVD trial despite reducing mortality. Disappointingly little improvement in exercise tolerance and persistence of chronic fatigue in heart failure concentrated attention on the periphery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The push, the pull and the periphery. 144 45

Inotropic support is often required for post-operative management of patients following mitral valve operation. The use of positive inotropes is limited by tolerance development and increase in myocardial oxygen demand. We have compared i.v. enoximone (E) (group E, n = 13), a recently developed phosphodiesterase (PDE) inhibitor, to the conventional i.v. therapeutics dopamine (D) and glyceroltrinitrate (G) in patients following mitral valve operation. The two groups were comparable in terms of physical and pre-operative haemodynamic data. Haemodynamic measurements including cardiac index (CI) determinations were recorded for the first 18 h post surgery in both groups. Group E received a bolus of 1 mg.kg-1 E followed by 4-20 micrograms.kg-1.min-1 (mean = 5 +/- 2 micrograms.kg-1.min-1) for 14 h according to therapeutic requirements, while group D received dopamine (4-10 micrograms.kg-1.min-1, mean = 3.8 +/- 1.9 micrograms.kg-1.min-1) and glyceroltrinitrate (0.5-5 micrograms.kg-1.min-1; mean = 4 +/- 2 micrograms.kg-1.min-1). Adrenaline was added if the MAP was below 60 mmHg or the CI was below 2.5 in both groups (range 50-500 ng.kg-1.min-1; mean E = 0.7 +/- 2 ng.kg-1.min-1; mean D = 2 +/- 2.8 ng.kg-1.min-1). Bolus injection of E resulted in a rise in CI from 2.6 to 3.21.min-1.m-2 (P less than 0.05) within 30 min, followed by a further rise to a maximum of 3.51.min-1.m-2 6 h post bolus. Termination of the E drip resulted in a drop of CI to baseline values (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enoximone, a post-operative inodilator in patients following mitral valve operation: a prospective and controlled study. 153 88

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


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