Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of levosimendan, a new myofilament Ca2+ sensitizer with phosphodiesterase (PDE)-inhibiting properties, on systemic and coronary hemodynamics and left ventricular (LV) systolic and diastolic function in conscious dogs with intact and blocked autonomic nervous system (ANS) reflexes. Twenty experiments were conducted in 10 dogs chronically instrumented for measurement of aortic and LV pressure, the peak rate of increase and decrease in LV pressure (+dP/dtmax and -dP/dtmin), subendocardial segment length, diastolic coronary blood flow (CBF) velocity, and cardiac output (CO). The slope (Mw) of the regional preload recruitable stroke work relation was used to assess myocardial contractility. Diastolic function was evaluated by -dP/dtmin, a time constant of isovolumic relaxation (tau), maximum segment lengthening velocity during rapid ventricular filling (dL/dtmax), and a regional chamber stiffness constant (Kp). Dogs were randomly assigned to receive levosimendan (0.5, 1.0, 2.0, and 4.0 micrograms.kg-1.min-1) with or without ANS blockade. On separate experimental days, systemic and coronary hemodynamics and LV pressure-segment length diagrams and waveforms were recorded after 10-min equilibration at each dose in the conscious ANS-intact or ANS-blocked state. Levosimendan increased heart rate (HR), CO, mean and diastolic CBF velocity, and pressure-work index (PWI, an estimate of myocardial oxygen consumption) and decreased LV end-diastolic pressure (EDP), systemic vascular resistance (SVR), end-systolic and end-diastolic segment length, and mean and diastolic coronary vascular resistance (CVR) in dogs with intact ANS function. Levosimendan-induced increases in HR and PWI and decreases in SVR were attenuated by ANS blockade. Levosimendan caused equivalent dose-dependent increases in Mw in ANS-intact and ANS-blocked dogs, consistent with a positive inotropic effect independent of ANS activity. Levosimendan decreased tau (e.g., 35 +/- 1 ms during control to 29 +/- 1 ms at the high dose) and increased the magnitude of LV -dP/dtmin in dogs with intact but not blocked ANS reflexes, suggesting that relaxation was enhanced by favorable changes in systemic hemodynamics or ANS activation and direct effects of this drug on lusitropic state. Levosimendan also increased dL/dtmax to a greater degree in ANS-intact dogs, indicating that improvement of rapid ventricular filling was also partially dependent on ANS tone. No changes in Kp were observed in either experimental group. The results indicate that levosimendan decreases preload and afterload and has positive inotropic and lusitropic properties. The actions of levosimendan on diastolic function are largely mediated by the ANS.
 ...
PMID:Systemic and coronary hemodynamic actions and left ventricular functional effects of levosimendan in conscious dogs. 747 41

Levosimendan is a novel inodilator that increases the calcium sensitivity of troponin C in a calcium-dependent way. Cardiac function (impedance cardiography, systolic time intervals), neurohumoral responses at rest and during exercise at 2 workloads, and peripheral blood flow (plethysmography) were studied in 14 healthy young men. Vehicle and 2 doses of levosimendan (6.5 micrograms/kg, low dose [LD]; and 25 micrograms/kg, high dose [HD]) were given intravenously in a crossover study. Measurements taken 15 minutes after a supine rest showed HD levosimendan shortened electromechanical systole (QS2i) by 16 ms maximally (p < 0.001), and decreased systemic vascular resistance by 25% (p < 0.001), compared with baseline values. Diastolic blood pressure fell by 9 mm Hg (p < 0.01). When the changes after vehicle were compared with the changes after HD levosimendan, the difference was 2.1 L/min after 25 micrograms/kg (p < 0.001), caused by an increase in stroke volume, with the heart rate being unaffected. Leg blood flow increased by 35% (p < 0.001). During exercise at the lower workload, HD levosimendan increased cardiac output by 1.5 L/min (p < 0.05), compared with that caused by vehicle, by an increase in heart rate, with the stroke volume being unchanged. Electromechanical systole was shortened significantly (20 ms, p < 0.001 after HD; 12 ms, p < 0.01 after LD). At the higher workload, no effects on electromechanical systole or cardiac output compared with that associated with administration of vehicle were seen, but the mean heart rate increased (p < 0.001, LD and HD) and mean diastolic blood pressure decreased (p < 0.01, HD).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Hemodynamic and neurohumoral effects of levosimendan, a new calcium sensitizer, at rest and during exercise in healthy men. 774 90

We examined the hemodynamic and left ventricular (LV) functional actions of dopamine with and without levosimendan in dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dtmax, subendocardial segment length, and cardiac output (CO). On different experimental days, dogs were randomly assigned to receive dopamine (2.5, 5.0, and 10.0 micrograms kg-1 min-1) in the absence and presence of levosimendan (0.125, 0.25, and 0.5 microgram kg-1 min-1) or levosimendan alone. Dopamine increased heart rate (HR), CO, stroke volume (SV), and pressure-work index (PWI) and decreased systemic vascular resistance (SVR). Dopamine also increased LV systolic and end-diastolic pressures (LVSP and LVEDP) and mean arterial pressure (MAP). Dopamine caused dose-related positive inotropic [increases in preload recruitable stroke work (Mw) and + dP/ dtmax] and lusitropic effects [decreases in the time constant of isovolumic relaxation (tau) and increases in maximum segment-lengthening velocity (dL/dtmax)]. Dopamine also increased the regional chamber thickness constant (Kp) concomitant with increases in LVEDP. In the presence of levosimendan, dopamine-induced increases in HR, PWI, CO, and SV and decreases in SVR were enhanced. Increases in MAP, LVSP, and LVEDP observed with dopamine alone were attenuated by the addition of levosimendan. Dopamine-induced increases in Mw and +dP/dtmax were enhanced by levosimendan. Reductions in tau and increases in dL/dtmax produced by dopamine were similar with and without levosimendan. However, levosimendan abolished increases in Kp caused by dopamine alone. Levosimendan alone caused dose-related improvements in indices of LV systolic and diastolic function. The results indicate that levosimendan potentiates the positive inotropic effects of dopamine in conscious, unsedated dogs, while attenuating the deleterious action of dopamine on chamber compliance.
 ...
PMID:Levosimendan potentiates the inotropic actions of dopamine in conscious dogs. 879 34

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.
 ...
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.
 ...
PMID:Dose-range study of a new calcium sensitizer, levosimendan, in patients with left ventricular dysfunction. 890 33

Levosimendan is a new myofilament calcium (Ca2+) sensitizer that increases myocardial contractility by stabilizing the Ca2+-bound conformation of troponin C. We tested the hypothesis that levosimendan enhances cardiac performance after cardiopulmonary bypass (CPB). Anesthesia was induced and maintained with midazolam, sufentanil, and vecuronium in 18 patients randomly assigned to receive levosimendan (18 or 36 microg/kg loading dose and 0.2 or 0.3 microg/kg/min infusion, respectively) or placebo 15 min before and continued for 6 h after CPB. Significant (p < 0.05) increases in heart rate (HR) and decreases in systemic vascular resistance (SVR) occurred 15 min after CPB in patients receiving placebo. Later increases in mean arterial pressure (MAP) and cardiac output (CO) and decreases in stroke volume (SV) and pulmonary vascular resistance also were observed. HR was greater in patients receiving high- but not low-dose levosimendan versus placebo immediately after CPB. MAP also was lower in patients treated with either dose of levosimendan compared with placebo after CPB. Levosimendan increased CO and decreased SVR (4.2 +/- 0.4 to 7.9 +/- 0.4 L/min and 1,150 +/- 99 to 512 +/- 42 dyn/s/cm5, respectively, 15 min after CPB; mean +/- SEM). CO and SV were higher and SVR was lower in patients receiving levosimendan versus placebo after CPB. No differences in arterial oxygenation and perioperative arrhythmias (Holter analysis) were observed between groups. The results indicate that levosimendan enhances cardiac performance after CPB in humans.
 ...
PMID:Levosimendan enhances cardiac performance after cardiopulmonary bypass: a prospective, randomized placebo-controlled trial. 1044 73

Although no universal definition exists, decompensated heart failure may be regarded as either a worsening of chronic heart failure or new-onset heart failure precipitated by an acute incident. Haemodynamic management of patients hospitalised with decompensated heart failure may include the administration of diuretics, vasodilators and positive inotropic agents. Until recently, these latter agents constituted the only drug class to produce a direct increase in stroke volume via enhanced myocardial contractility. However, despite their short-term benefits, the clinical utility of inotropic agents is compromised by their potentially deleterious effects on calcium handling and oxygen consumption, resulting in an increased risk of serious ventricular arrhythmias and death. In contrast, calcium sensitisers enhance cardiac performance without affecting calcium movement and, therefore, are potentially associated with a reduced risk of rhythmic disturbances. These agents constitute a heterogeneous group of compounds with different affinities for calcium sensitisation. Levosimendan is a potent calcium sensitiser with vasodilating properties that has been shown to provide symptomatic and haemodynamic improvement with no increase in oxygen consumption. Calcium sensitisation is therefore emerging as a promising treatment approach in this challenging therapeutic area.
 ...
PMID:Pharmacotherapeutic approaches for decompensated heart failure: a role for the calcium sensitiser, levosimendan? 1255 10

The finely-tuned increases and decreases in the intracellular calcium levels in myocytes ultimately regulate the contraction and relaxation of the heart. Therapeutic agents can improve or interfere with this delicate balance. Calcium sensitizers enhance cardiac contraction by improving the use of calcium that is available, rather than by inundating the cell with excessive calcium, as is the case with traditional inotropes. With the sensitizing mechanism, the energy cost of contraction is maintained at a near-normal level, and the threat of arrhythmias and sudden death is low. Levosimendan is the first calcium sensitizer to become available for the treatment of patients with acute heart failure. In recent clinical studies, levosimendan increased cardiac output and stroke volume without significantly increasing oxygen demand. By its additional action as a vasodilator (via potassium channel opening), levosimendan also corrects the hemodynamic decompensation, thus lowering the pulmonary capillary wedge pressure and systemic vascular resistance. Furthermore, levosimendan increases the coronary circulation thus leading to an improved function of the stunned myocardium and lessened ischemia. Taken together, levosimendan's primary calcium-sensitizing action, along with its complementary vasodilator properties, make this new drug a highly promising agent for the treatment of patients with acute heart failure.
 ...
PMID:Is calcium sensitization the best strategy to improve myocardial contractility in acute heart failure? 1463 67

Heart failure is the most common malignant disease in the developed world. Levosimendan (Simdax) is a novel intravenous agent that exerts inotropic effects through sensitization of myofilaments to calcium and vasodilator effects by opening ATP-dependent potassium channels on vascular smooth muscle. Infusion of levosimendan increases cardiac output due to an increase in stroke volume and heart rate, with a fall in pulmonary capillary wedge pressure. It has an active metabolite with a half-life of about 80 h, therefore infusions of 6 to 24 h result in hemodynamic effects that persist for 7 to 10 days. Preliminary observations suggest that a single infusion of levosimendan lasting 6 to 24 h in patients with severe heart failure due to left ventricular systolic dysfunction results in hemodynamic changes, symptomatic benefit and a reduction in morbidity and mortality over the following 2 to 4 weeks compared with placebo in one study and with dobutamine in another. Long-term follow-up suggests no loss of this early benefit over 6 months. Levosimendan is licensed for the treatment of decompensated heart failure in many countries but not in North America. Further large trials are being conducted comparing levosimendan with placebo and with dobutamine in patients with severe heart failure and left ventricular systolic dysfunction. If these studies confirm the benefits of levosimendan, then it may become routine therapy for the management of severe heart failure.
 ...
PMID:Levosimendan: first in a new class of inodilator for acute and chronic severe heart failure. 1503 9

Following cardiac surgery, low-output syndrome is relatively common. Since this condition can lead to serious consequences, this postsurgical, low-output state should be reversed whenever possible. Patients with low-output syndrome need drug and fluid management aimed at enhancing cardiac contractility and at facilitating optimal myocardial loading. The objective of this pilot study was to evaluate whether benefits of levosimendan, a new calcium-sensitizing agent approved for treatment of patients with acute exacerbation of chronic heart failure, could be extended to patients with low-output syndrome following cardiac surgery. For this study, each patient was given levosimendan as a loading dose of 12 microg/kg over 10 minutes, followed by a continuous infusion of 0.1 microg/kg/min for 12 hours. Of 11 postsurgical patients with severely impaired cardiac output and hemodynamic compromise, 8 patients (73%) showed evidence of combined hemodynamic improvement (> 30% increase in cardiac index and PCWP corrected to < 18 mmHg) within 3 h after the start of levosimendan infusion. Specifically, cardiac index and stroke volume were significantly increased, while mean arterial pressure, indexed systemic vascular resistance, mean pulmonary pressure, right arterial pressure, and pulmonary capillary wedge pressure were all significantly lowered. Taken together, such changes showed enhanced cardiac output along with significantly decreased preload and afterload--conditions associated with recovery of cardiac function. Levosimendan is thus highly favorable for short-term treatment of patients with low cardiac output following cardiac surgery.
 ...
PMID:Hemodynamic effects of levosimendan in patients with low-output heart failure after cardiac surgery. 1512 78


1 2 3 Next >>