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)

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.
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PMID:Systemic and coronary hemodynamic actions and left ventricular functional effects of levosimendan in conscious dogs. 747 41

1. The haemodynamic effects of a novel cardiotonic drug, levosimendan, which has both calcium-sensitizing and phosphodiesterase III (PDE III) inhibitory properties, were studied in conscious dogs in which heart failure had been induced by prolonged cardiac pacing in the presence of aortic constriction. These effects were compared with those in sham-operated dogs with essentially normal cardiac function. 2. Eighteen mongrel dogs were instrumented for the measurement of left ventricular pressure (LVSP, LVEDP) and contractile function (dP/dt; dP/dt/P). In twelve dogs a balloon catheter, positioned in the thoracic aorta, was inflated producing an approximate 60% reduction in effective aortic diameter. Twenty min later rapid ventricular pacing (240 beats mean-1) was commenced and maintained for 48 h by means of a bipolar pacing electrode introduced into the right ventricle. This electrode served also for recording changes in the endocardial electrogram in the absence of pacing. Six of these dogs were used to evaluate the haemodynamic changes of pacing-induced heart failure; a further six of these dogs the haemodynamic changes elicited by levosimendan under these conditions. Six sham-operated dogs (group 2) served as controls. 3. In six dogs (group 1) the haemodynamic alterations were assessed after the development of heart failure. In the presence of aortic constriction, 48 h continuous rapid cardiac pacing resulted in a marked deterioration in left ventricular function which remained stable for at least 48 h after cessation of pacing. Thus, there was a marked reduction in LVSP (15%), +dP/dtmax (35%), -dP/dtmax (36%) and also in dP/dt/P (29%), whereas LVEDP was increased considerably (from 6.4 +/- 1.4 to 20.0 +/- 2.2 mmHg). A marked elevation occurred in endocardial ST-segment (138%), lasting for 20 min.4. Levosimendan was administered intravenously in doses of 0.005, 0.01 and 0.03 micromol kg-1 to 2 groups of conscious dogs. In the sham-operated dogs (group 2), only the higher dose (0.03 micromol kg-1)produced significant increases in LVSP (19%), + dP/dtmax (37%), and in dP/dt/P (32%). In dogs with heart failure (group 3) doses of 0.005, 0.01 and 0.03 micromol kg-1 levosimendan resulted in an improve mentin +dP/dtmax (26%, 38% and 49%), -dP/dtmax (20%, 25% and 38%) and in dP/dt/P (19%, 34%and 50%) and reduction in the elevated LVEDP (from 20 =/- 2.2 mmHg to 16 +/- 1.0, 10 +/- 1.3 and 9 +/- 1.0 mmHg, respectively).5. Levosimendan proved to be a potent cardiotonic drug at the doses used, and was approximately three times more effective under conditions of impaired left ventricular function than in normal hearts.
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PMID:Cardiovascular effects of the calcium sensitizer, levosimendan, in heart failure induced by rapid pacing in the presence of aortic constriction. 773 92

A new cardiotonic agent, (R)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl] hydrazono]propanedinitrile (Levosimendan), has been developed and screened for its ability to bind to cardiac troponin C. In perfused hearts, low concentrations of 0.03 or 0.1 mumol/L Levosimendan increased +dP/dt, but did not affect the speed of relaxation and produced only a slight increase in spontaneous heart rate in the hearts perfused with 0.1 mumol/L of the drug. In these same hearts, perfusion with 0.03 mumol/L Levosimendan did not alter the 32P incorporation into troponin I or C protein, whereas a slight but significant increase was noted for phospholamban, with no detectable change in tissue cAMP levels. Administration of 0.1 or 0.3 mumol/L Levosimendan significantly increased myocardial cAMP levels as well as the phosphorylation of phospholamban, troponin I, and C protein. Levosimendan (0.03 to 10 mumol/L) reversibly increased force generated by detergent-extracted fiber bundles over a range of submaximally activating free Ca2+ concentrations with no significant effect on maximum force or on Ca2+ binding to myofilament troponin C. There was no direct effect of Levosimendan on Ca2+ uptake by vesicles of sarcoplasmic reticulum (SR). In contrast, under conditions optimal for cAMP-dependent phosphorylation, Levosimendan slightly but significantly lowered the concentration of Ca2+, yielding half-maximal uptake rates by the SR vesicles. Our results indicate that at low concentrations Levosimendan acts preferably as a Ca2+ sensitizer, whereas at higher concentrations its action as a phosphodiesterase inhibitor contributes to the positive inotropic effect.
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PMID:Effects of Levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart. 778 68

The effects of various calcium sensitizers on myosin-actin crossbridge kinetics were evaluated in intact, paced guinea-pig papillary muscle by analysing the velocity of the development of isometric tension (dT/dt) in detail. The effect on association (the whole sequence of events from troponin onward) and dissociation rates of crossbridges was estimated from the rising phase and from the early decay phase of the normalized dT/dt curve. Levosimendan, a calcium sensitizer acting through troponin C, accelerated the proportional association rate and decelerated the dissociation rate of crossbridges. The effect of levosimendan on crossbridge kinetics occurred before the peak twitch tension was achieved. Thus, the compound did not change the actual relaxation phase of twitch tension. Since the effect on the association was more pronounced than on the dissociation of crossbridges, levosimendan shifted the entire twitch tension curve to the left. Based on the dissociation rate analysis levosimendan seems to act preferentially as a calcium sensitizer at low concentrations. At high concentrations the phosphodiesterase III (PDE III) inhibitory properties of levosimendan modulated its effect on the early relaxation processes. In contrast, PDE III inhibition is probably the primary mechanism of action for MCI-154. Pimobendan, and EMD 53998 at low concentrations, whereas their direct effects on crossbridge kinetics contributed to the positive inotropic action at high concentrations. The calcium sensitizing mechanisms of these compounds seemed to be based almost exclusively on the decelerating effect on dissociation of crossbridges.
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PMID:Troponin C-mediated calcium sensitization by levosimendan accelerates the proportional development of isometric tension. 857 32

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

Calcium sensitizers may influence myocardial energetics by their action on calcium turnover and on crossbridge behavior. Using a myothermal method, the effects of the Ca2+ sensitizer EMD-53998 on calcium cycling, crossbridge behavior, and myocardial energy turnover were compared with the effects of an increase in extracellular calcium from 1.25 to 7.5 mM and with the effects of the catecholamine isoproterenol. All three inotropic interventions increased isometric force development in right ventricular rabbit papillary muscles. Relaxation time was decreased with isoproterenol, unchanged with high calcium, and increased with EMD 53998. Calcium cycling-related energy consumption, as measured by tension-independent heat, increased by 234% with high calcium, by 439% with isoproterenol, and by 77% with EMD 53998. In contrast to high calcium and isoproterenol, EMD 53998 increased economy of crossbridge cycling by increasing the force-time integral of the individual crossbridge cycle. The data indicate that EMD 53998 acts by phosphodiesterase inhibition and myofilament calcium sensitization. The latter effect is in part mediated by alteration of crossbridge behavior. Because of its effects on calcium cycling and crossbridge function myocardial energy turnover was reduced significantly with EMD 53998, whereas energy turnover was unchanged with high calcium and was increased with isoproterenol. The new calcium sensitizer levosimendan was investigated in isolated failing human myocardium. Levosimendan dose-dependently increased isometric tension. The inotropic effect was associated with increased rate of relaxation and reduced relaxation time. Measurements of intracellular calcium using the photoprotein aequorin suggest that levosimendan acts by increasing myofilament calcium sensitivity and by increasing cAMP due to phosphodiesterase inhibition. However, the contribution of the cAMP system to the action of levosimendan appears to be rather small. Therefore, the finding of a positive lusitropic effect of levosimendan may be consistent with the notion that levosimendan binds to troponin-C and increases calcium sensitivity only at high (systolic) intracellular calcium concentrations.
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PMID:Effects of calcium sensitizers on intracellular calcium handling and myocardial energetics. 890 30

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

Ca2+-sensitising agents offer a new approach to the treatment of congestive heart failure. This study examined the effects of the Ca2+-sensitising agent, levosimendan, on contraction and [Ca2+]i in guinea-pig ventricular myocytes. Levosimendan 100 nM produced an increase in cell shortening without affecting the [Ca2+]i transient or the Ca2+ content of the sarcoplasmic reticulum. 1 microM levosimendan increased the rate of decay of the [Ca2+]i transient and increased the Ca2+ content of the sarcoplasmic reticulum. These results suggest that at therapeutically relevant concentrations levosimendan can produce a significant inotropic effect without affecting [Ca2+]i but at higher concentrations may also inhibit phosphodiesterase.
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PMID:The effects of levosimendan on [Ca2+]i in guinea-pig isolated ventricular myocytes. 945 Jun 21

Effects of levosimendan on myocardial contractility and Ca2+ transients were assessed in the ventricular myocardium of the rabbit. Levosimendan at and above 0.1 microM had a concentration-dependent positive inotropic effect (PIE) on isolated papillary muscles that had been loaded with aqeuorin. The maximum inotropic response to levosimendan at 3 microM was approximately 20% of the maximum response to isoproterenol (ISOmax), whereas the maximum increase in the amplitude of Ca2+ transients was approximately 11% of ISOmax. For a given PIE, levosimendan increased the amplitude of Ca2+ transients much less than an elevation of [Ca2+]o. Levosimendan did not prolong the relaxation time. Similar results were obtained in single ventricular cardiomyocytes that had been loaded with indo-1. In the presence of the muscarinic receptor agonist carbachol, both the PIE and the increase in the Ca2+ transient induced by levosimendan were markedly attenuated. During wash-out of both carbachol and levosimendan, the contractile force increased conspicuously with little change in the amplitude of Ca2+ transients, an indication that the increase in myofibrillar sensitivity to Ca2+ ions elicited by levosimendan was susceptible to carbachol. Levosimendan at and above 0.03 microM shifted the concentration-response curve for isoproterenol to the left. Levosimendan had a positive chronotropic effect at 0.01 microM and higher in the isolated right atrium of the rabbit. These findings indicate that, in addition to the increase by levosimendan of the sensitivity of contractile proteins to Ca2+ ions, the accumulation of cyclic AMP due to the phosphodiesterase-inhibitory action of levosimendan might contribute to the PIE of this drug.
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PMID:Effects of levosimendan on myocardial contractility and Ca2+ transients in aequorin-loaded right-ventricular papillary muscles and indo-1-loaded single ventricular cardiomyocytes of the rabbit. 968 86

Levosimendan is a pyridazinone-dinitrile derivative belonging to a new class of cardiac inotropic drugs, Ca++ sensitizers. Levosimendan is also a vasodilator both in vitro and in vivo, but its mechanism is not well understood. The cardiac target protein of levosimendan, troponin C, is a Ca++-binding EF-hand protein. This raises the possibility that levosimendan may also interact with smooth muscle EF-hand proteins, such as, calmodulin, the regulatory myosin light chains, or S100 proteins. We investigated the effects of levosimendan on [Ca++]i, and force in porcine coronary arteries, with receptor-mediated (U46619) or KCl stimulation. At high levels of stimulation, levosimendan decreased force without changing or increasing [Ca++]i, measured with the Ca++-sensitive fluorescent probe fura-2 in the intact artery. With lower levels of U46619, levosimendan (1 microM) lowered force by 70% and reduced [Ca++]i by 38%. The relationship between force and [Ca++]i for KCl stimulation are significantly rightward shifted, indicating Ca++ desensitization by levosimendan. In contrast, the phosphodiesterase III inhibitor, milrinone, does not shift the force-Ca++ relations but elicits relaxation via lowering [Ca++]i. There was little change in pHi, indicating that the Ca++ desensitization by levosimendan was not attributable to decreasing pHi. Levosimendan relaxes coronary arteries and lowers [Ca++]i by mechanisms different than milrinone. Our results indicate a lowering of [Ca++]i by levosimendan consistent with opening of potassium channels and a relaxation that is independent of [Ca++]i. Our evidence points to a novel mechanism that might involve the direct effect of levosimendan on the smooth muscle contractile or regulatory proteins themselves.
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PMID:Levosimendan, a calcium sensitizer in cardiac muscle, induces relaxation in coronary smooth muscle through calcium desensitization. 986 86


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