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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitral valve surgery may be complicated by a post-operative low output state requiring inotropic support, and a wide variety of factors may influence the choice of agents used to treat this condition. The authors have examined and compared the haemodynamic effects of the highly specific phosphodiesterase inhibitor enoximone, and the adrenergic agents dobutamine and dopamine in patients undergoing mitral valve surgery. Enoximone, 0.5 mg kg-1 bolus, followed by a continuous infusion of 5 micrograms kg-1 min-1, was compared against dobutamine, 7 micrograms kg-1 min-1, and dopamine, 5 micrograms kg-1 min-1, with the protocol allowing for an increase in the infusion rate by a factor of two if clinical and haemodynamic measurements indicated. All 25 patients receiving enoximone were successfully weaned from cardiopulmonary bypass at the first attempt, with significant increases in cardiac index and stroke index, combined with little or no change in heart rate or pulmonary artery pressures and a highly significant reduction in systemic vascular resistance, and a reduction in mean arterial pressure. Three of the 25 patients receiving dobutamine were withdrawn from the study because of inadequate haemodynamic response, while the remaining 22 patients demonstrated significant increases in heart rate, cardiac index and stroke index, with a reduction in systemic vascular resistance. Nine of the 25 patients receiving dopamine failed to respond adequately, while the remaining 16 demonstrated an increase in heart rate and cardiac index but with little change in stroke index and a modest reduction in systemic vascular resistance. Enoximone has been shown to be a highly effective first-line inotrope in patients following mitral valve surgery with significant advantages over dobutamine and dopamine.
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PMID:Haemodynamic effects and comparison of enoximone, dobutamine and dopamine following mitral valve surgery. 822 51

We have investigated the circulatory effects of halothane and isoflurane in the presence of the phosphodiesterase inhibitor, enoximone, in 20 patients, ASA class III, aged 40-70 yr, undergoing coronary artery bypass grafting. After induction of anaesthesia (midazolam, fentanyl, etomidate and pancuronium) all patients received enoximone 0.5 mg kg-1, followed, 10 min later, by either halothane 1 MAC (group I; n = 10) or isoflurane 1 MAC (group II; n = 10). Haemodynamic variables were measured and blood samples (arterial and mixed venous) were obtained before (control, t0), 5 (t1) and 10 (t2) min after the injection of enoximone and immediately (t3) and 5 (t4) min after steady state conditions with halothane or isoflurane, as verified by the end-expiratory concentration. Heart rate, mean arterial pressure (MAP), mean pulmonary artery pressure, pulmonary capillary wedge pressure and right atrial pressure were recorded. Cardiac (CI) and stroke volume indices, systemic (SVR) and pulmonary vascular resistance, oxygen availability (QO2), oxygen consumption and oxygen extraction rate were calculated using standard formulae. MAP decreased significantly in both groups after bolus injection of enoximone (group I: 11%; group II: 7%). Under steady state conditions with the volatile anaesthetics, a further significant decrease in MAP was observed (group I: 12%; group II: 12%). Enoximone produced a significant increase in CI (group I: 25%; group II: 27% compared with control). After administration of isoflurane, CI remained essentially unchanged, while halothane decreased CI significantly by 20%. In both groups, SVR decreased significantly after administration of enoximone (group I: 26%; group II: 24%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Haemodynamic changes produced by inhalation anaesthetics in the presence of phosphodiesterase inhibition. 849 3

Amrinone, a phosphodiesterase III inhibitor, is known to exert inotropic and vasodilating effects. This study was undertaken to investigate the hemodynamic effects and optimal dose of amrinone in patients undergoing coronary artery bypass surgery. Seventeen patients with ejection fraction > 0.45 were included. In both group B and C, amrinone 0.5 mg.kg-1 was administered in the venous reservoir near the end of cardiopulmonary bypass (CPB), and doses of 1 and 5 micrograms.kg-1.min-1 by an intravenous infusion. Additional group of A did not receive amrinone. In group B, amrinone increased cardiac index by 79% and stroke index by 81% while decreased mean arterial pressure by 19% and systemic vascular resistance by 59% in comparison with group A. Heart rate did not increase. In group C, changes of hemodynamic variables were almost the same compared with group B. These data suggests that amrinone improves left ventricular performance without increasing myocardial oxygen demand while recovering from CPB. However, a high dose of amrinone should be used in combination with catecholamines because its vasodilating action is potentiated by hyperdynamic state after CPB.
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PMID:[Hemodynamic effects of amrinone during emergence from cardiopulmonary bypass]. 858 58

Low heart stroke volume syndrome is clinically manifested with hypoperfusion of all body systems. Inotropic or mechanical support is applied. Acute heart failure is one of the most important complications after open heart surgery. Catecholamines have been up to non considered as a therapy of choice for the acute heart failure. Effectiveness of catecholamines could be limited with some side effects. Phosphodiesterase inhibitors promise a new therapeutic approach. PDE III primary act through phosphodiesterase inhibition which leads to a rise of aAPM levels. Thus they show positive inotropic and lusitropic effects, which could be monitored by occlusive pulmonary capillary pressure values. Amrinone is obviously superior to inotropic catecholamines.
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PMID:[Hemodynamic effects of amrinone, dobutamine and dopamine in the cardiac low output syndrome following open-heart surgery]. 864 47

In 1991 and 1992, we introduced the new phosphodiesterase-III-inhibitor, enoximone, in the treatment of cardiac low-output-syndromes in the early phase after valve replacement or coronary bypass grafting. We introduced enoximone in cases which met the following criteria: cardiac index < or = 2.4 l/min/m2; systolic arterial pressure < or = 90 mmHg; left ventricular filling pressure > or = 20 mmHg despite the use of dopamine (> or = 12 micrograms/kg/ min); epinephrine (> or = 0.12 microgram/kg/min) and glyceroltrinitrate (1 microgram/kg/min). After clarification of preoperative risk factors and postoperative complications, retrospective evaluation of complete haemodynamic monitoring in patients after valve replacement (14 out of 86) and patients after coronary bypass grafting (22 out of 228) led to the following conclusions. Enoximone is of essential importance for the treatment of cardiac low-output at the end of extracorporeal circulation, particularly in cases complicated by preoperative myocardial deterioration. The use of enoximone is especially effective combined with beta-sympathomimetics as a result of elevation of cAMP-levels in two ways: by stimulation of beta-adrenoceptors directly and by inhibition of phosphodiesterase. Cardiac indices early after bypass, compared with measurements taken before bypass, reveal a clear rise indeed caused by increase in heart rate. Only in patients who underwent coronary bypass grafting did we observe a moderate increase in stroke volume indices. The therapeutic principle of using vasodilators--to lower peripheral resistance for improving stroke volume --appears to be effective immediately after extracorporeal circulation only in part. The vasodilating effect of enoximone has to be constantly compensated for by volume supplementation and alpha-mimetic stimulation, especially after valve replacement surgery. In contrast to this, we continued the application of glyceroltrinitrate in about 25% of the cases. Coronary surgery patients tolerated the vasodilating action particularly well; consequently, despite inotropic stimulation to a high degree, these patients showed no additional signs of ischaemia. Based on our therapeutic measures, the therapy led to very good short-term results. However, this therapeutic regime failed in patients suffering from extended myocardial infarction or irreversible pulmonary hypertension.
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PMID:[Enoximone--clinical experiences in heart surgery]. 876 97

We examined and compared the effects of levosimendan, a new myofilament calcium sensitizer with phosphodiesterase inhibiting activity, pimobendan, and milrinone on left ventricular-arterial coupling and mechanical efficiency in 21 experiments performed in open-chest, barbiturate-anesthetized dogs instrumented for measurement of aortic and left ventricular (LV) pressure (micromanometer-tipped catheter), +dP/dt, and LV volume (conductance catheter). Myocardial contractility was assessed with the end-systolic pressure-volume relation (Ees) and preload recruitable stroke work (Msw) generated from a series of differentially loaded LV pressure-volume diagrams. LV-arterial coupling and mechanical efficiency were determined by the ratio of Ees to effective arterial elastance (Ea; the ratio of end-systolic arterial pressure to stroke volume) and the ratio of stroke work (SW) to pressure-volume area (PVA), respectively. Levosimendan (0.75, 1.5, and 3.0 micrograms.kg-1.min-1) significantly (p < 0.05) increased heart rate, +dP/dt, and ejection fraction (EF) and decreased mean arterial pressure (MAP), pressure-work index (PWI; an estimate of myocardial-oxygen consumption), and LV systolic and end-diastolic pressures (LVSP and LVEDP) and volumes (EDV and ESV). Levosimendan-induced augmentation of myocardial contractility (Ees, Msw and +dP/dt) and reductions in LV afterload (Ea) caused increases in the Ees/Ea ratio (0.61 +/- 0.10 during control to 3.3 +/- 0.7 during the high dose) consistent with enhancement of LV-arterial coupling. Levosimendan increased SW/PVA (0.48 +/- 0.05 during control to 0.84 +/- 0.04 during the high dose), indicating this drug improves the transfer of myocardial potential energy to external work. Levosimendan also increased the ratio of SW to PWI (109 +/- 18 during control to 255 +/- 50 mmHg.min.100g during the high dose), suggesting that myocardial metabolic efficiency was improved as well. Like levosimendan, pimobendan and milrinone (10, 20, and 40 and 1.0, 2.0, and 4.0 micrograms.kg-1.min-1, respectively) increased HR, +dP/dt, EF, Ees, and Msw and decreased MAP, LVSP, LVEDP, EDV, ESV, and Ea. In contrast to levosimendan, neither agent reduced PWI. Pimobendan and milrinone caused dose-related increases in Ees/Ea, SW/PVA, and SW/PWI. The results indicate that levosimendan, pimobendan, and milrinone augment myocardial contractility, produce venous and arteriolar vasodilation, and enhance LV-arterial coupling and mechanical efficiency in open-chest, barbiturate-anesthetized dogs.
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PMID:Comparison of the effects of levosimendan, pimobendan, and milrinone on canine left ventricular-arterial coupling and mechanical efficiency. 887 79

Levosimendan, a new drug that sensitizes troponin-C to calcium and selectively inhibits phosphodiesterase III, was administered to 24 patients with ischemic heart disease and ejection fraction below 40%. In a placebo-controlled, crossover, double-blind study, each patient received two intravenous doses of levosimendan on 2 consecutive study days. The doses were 0.25 mg (n = 6), 0.5 mg (n = 11), 1 mg (n = 12), 2 mg (n = 12), and 4 mg (n = 5). After 0.25 mg and 0.5 mg, cardiac output increased by 0.49-0.67 L/min (p < 0.05) due to an increase in stroke volume of 6-11 ml. After 2 and 4 mg, cardiac output increased by 0.61-0.88 L/min due to an increase in heart rate of 6-12 beats/min. The baseline filling pressures, i.e., right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP), were within the normal range. RAP decreased significantly (p < 0.05) after 2 and 4 mg and PCWP after 0.5, 1, 2, and 4 mg. The most profound decreases were observed 10 min after infusion of 4 mg, from 5.0 to 3.2 mm Hg in RAP and from 9.8 to 6.0 mm Hg in PCWP. Total peripheral resistance decreased significantly only after 2 and 4 mg, by 13 and 21%, respectively. However, there were no statistically significant changes in pulmonary vascular resistance. It is concluded that levosimendan has a hemodynamically favorable action after 0.25 and 0.5 mg but that decreases in filling pressures probably prevented the increase in stroke volume and caused a reflex increase in heart rate after 2 and 4 mg.
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PMID:Dose-range study of a new calcium sensitizer, levosimendan, in patients with left ventricular dysfunction. 890 33

We examined the effects of a novel phosphodiesterase III inhibitor, olprinone, on the cardiohemodynamics and plasma hormones in conscious pigs with pacing-induced heart failure. After pacing for 5-10 days, cardiac output (CO) decreased from 2.25 +/- 0.17 to 1.67 +/- 0.13 L/min (n = 8, p < 0.01) and stroke volume (SV) decreased from 20.1 +/- 2.1 to 12.0 +/- 1.6 ml (n = 8, p < 0.01), whereas left arterial pressure (LAP) increased from 2.8 +/- 1.2 to 16.7 -/+ 0.9 mm Hg (n = 7, p < 0.001) and systemic vascular resistance (SVR) increased from 38.7 +/- 3.5 to 49.8 +/- 4.2 mm Hg/L/min (n = 8, p < 0.01). Sequential intravenous infusions of 0.03, 0.3, and 3.0 microg/kg/min of olprinone at 30-min intervals to eight pigs caused dose-dependent increases in the decreased CO, SV, and maximal rate of rise in left ventricular pressure (LV dP/dt(max)) and decreased the elevated LAP and SVR. Olprinone at 3.0 microg/kg/min maximally increased CO, SV, and LV dP/dt(max) by 40.0 +/- 10.8% (p < 0.05 vs. vehicle), 25.6 +/- 6.9% (p < 0.05), and 43.9 +/- 11.2% (p < 0.01), respectively, and brought about a slight increase in heart rate and decreases in LAP and SVR, by 35.9 +/- 7.3% (p < 0.001) and 27.9 +/- 4.8% (p < 0.01), respectively. Olprinone did not affect the rate-pressure product. In addition, olprinone produced significant decreases in the plasma levels of atrial natriuretic peptide and cyclic guanosine monophosphate, with no changes in the plasma levels of cyclic adenosine monophosphate and catecholamines or plasma renin activity. These findings indicate that the short-term intravenous infusions of olprinone ameliorated the decreased left ventricular function without affecting myocardial oxygen consumption or the sympathetic nervous system in conscious pigs with heart failure.
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PMID:Effects of a new cardiotonic phosphodiesterase III inhibitor, olprinone, on cardiohemodynamics and plasma hormones in conscious pigs with heart failure. 923 57

As illustrated in Figure 1, a disturbance of the intracellular Ca2+ homeostasis is thought to be a common pathogenic factor for the generation of secondary nerve cell damage that develops after brain trauma or stroke or during the course of neurodegenerative diseases. A neuronal Ca2+ overload which may result from an excessive glutamate-evoked membrane depolarization and consecutive Ca2+ influx as well as from an activation of metabotropic receptors and consecutive intracellular Ca2+ mobilization is known to have direct toxic effects on the cytoskeleton and the cell metabolism of neurons. In addition, a Ca(2+)-dependent activation of glial cells along with the loss of physiologically required mature astrocyte functions and with the acquisition of potentially neurotoxic microglial properties, has more recently been recognized as an additive pathogenic factor. This may provide an effective target for pharmacological interference. Specifically, the reinforcement of an endogenous homeostatic regulator, which obtained its sophisticated know-how during evolution, may provide a neuroprotective therapy which can handle the complexity of the pathological process with a minor risk of pharmacological side effects. Adenosine is such an ancient molecular signal that acts on both neurons and glial cells. In neurons, adenosine activates K+ and Cl- conductances, which limits synaptically evoked depolarization, thus counteracting the Ca2+ influx through voltage-dependent and NMDA receptor-operated ion channels. This A1 receptor-mediated effect seems to be the major action by which adenosine adds directly to the protection of neurons against Ca(2+)-dependent damage. In glial cells, the prevalent effect of adenosine is its regulatory influence on the Ca2+ and cAMP-dependent molecular signaling that determines the cellular proliferation rate, the differentiation state and related functions. When mimicking the activation of metabotropic glutamate receptors in cultures of immature rat astrocytes, which largely resemble pathologically activated astrocytes, a transient Ca2+ mobilization was initiated by adenosine. This A1 receptor-mediated Ca2+ signal caused a prolonged potentiation of the A2 receptor-mediated intracellular cAMP rise. An experimentally sustained enhancement of the cAMP signaling initiated the differentiation of cultured astrocytes and the new expression of K+ and Cl- channels which are required for the physiological astrocyte function to maintain the extracellular ion homeostasis. Evidence is accumulating that a strengthening of the cAMP signaling, which can be achieved by adenosine agonists and also by the pharmacon propentofylline (an adenosine uptake blocker and phosphodiesterase inhibitor), stimulates the mRNA production of neurotrophic factors in astrocytes. In cultured microglial cells, several days' treatment with adenosine agonists or propentofylline markedly inhibited their proliferation rate, the in vitro spontaneously occurring transformation into macrophages and their particularly high formation of free oxygen radicals. Adenosine agonists also depressed the release of the potentially toxic cytokine TNF alpha and induced programmed cell death in immunologically activated microglial cells. We conclude that a pharmacological reinforcement of the endogenous cell modulator adenosine may provide neuroprotection by counteracting neuronal Ca2+ overload, by depressing potentially neurotoxic microglial functions and by regaining physiologically required properties of differentiated astrocytes. Further information about the influence of adenosine on the molecular signaling and on ischemic brain damage is given in Refs. 37 and 38, and about the implicated possible relevance for the treatment of stroke in Ref. 39.
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PMID:Protective mechanisms of adenosine in neurons and glial cells. 936 70

1. To date no study has described the cardiovascular effects of increased myofilament Ca2+ responsiveness in awake animals both under resting conditions and during treadmill exercise. In the present study we therefore investigated the systemic, pulmonary and coronary haemodynamic actions of the Ca2+ sensitizer EMD 57033 in 16 chronically instrumented awake pigs at rest and during treadmill exercise, and compared these to the haemodynamic actions of the Ca2+ sensitizer/phosphodiesterase inhibitor pimobendan. 2. Under resting conditions EMD 57033 (0.2, 0.4 and 0.8 mg kg(-1) min(-1), i.v.) produced dose-dependent increases in LVdP/dt(max) (up to 65+/-17% (mean+/-s.e.mean), P < or = 0.05) and stroke volume (up to 20+/-3%, P < or = 0.05), with an increase in heart rate only after the highest dose (22+/-5%, P < or = 0.05), while mean aortic blood pressure and LVdP/dt(min) were not altered. EMD 57033 had also no effect on pulmonary vascular resistance, but produced dose-dependent decreases in systemic vascular resistance (32+/-4%, P < or = 0.05), and coronary vascular resistance (44+/-2%, P < or = 0.05). These effects were essentially unchanged when animals were pretreated with non-selective beta-adrenoceptor blockade, indicating that phosphodiesterase inhibition did not contribute to the positive inotropic actions of EMD 57033. 3. During exercise at 2, 3, and 4 km h(-1), the positive inotropic actions of EMD 57033 gradually waned at higher levels of exercise. This may have been caused by the exercise-induced increase in beta-adrenergic activity, because after pretreatment with propranolol the positive inotropic actions of EMD 57033 were preserved at all levels of exercise. In contrast, the positive inotropic and chronotropic effects of pimobendan were amplified during exercise, but were abolished (at rest) or markedly attenuated (during exercise) after pretreatment with propranolol. 4. The responses to EMD 57033 during exercise after combined alpha- and beta-adrenergic receptor blockade were not different from those after beta-adrenergic receptor blockade alone, indicating that the positive inotropic actions of EMD 57033 were not mediated via or did not depend on intact alpha-adrenergic receptor activity. 5. In conclusion, EMD 57033 increases left ventricular myocardial contractility in awake pigs. During exercise this effect is partially offset by the increased beta-adrenergic activity, with no effect of alpha-adrenergic activity, suggesting that EMD 57033 may be most effective in patients with severe loss of beta-adrenergic responsiveness.
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PMID:Cardiovascular effects of the novel Ca2+-sensitiser EMD 57033 in pigs at rest and during treadmill exercise. 942 Dec 71


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