Biomedical subjects

Klara Brixius

Publications and source records attributed to Klara Brixius.

32 records · Page 2Linked to original sources

PubMed2005

Increased vascular selectivity and prolonged pharmacological efficacy of the L-type Ca2+ channel antagonist lercanidipine in human cardiovascular tissue.

1. The present study investigates the vasoselectivity of lercanidipine (LER), a 1,4-dihydropyridine calcium channel blocker, compared with amlodipine (AML) and nifedipine (NIF) in human cardiovascular tissue. Experiments were performed either in human left ventricular failing myocardium (orthotopic heart transplants) or in isolated right atrial trabeculae and isolated vessel preparations of arteria mammaria obtained from patients undergoing aortocoronary bypass operation. 2. The obtained rank order for the L-type Ca2+ channel affinity in human tissue was LER > NIF >or= AML. Lercanidipine had the lowest negative inotropic efficacy (1 micromol/L LER: 60.3% basal < AML: 79.1% basal < NIF: 92.4 basal) and potency (IC50 NIF: 3.5 nmol/L < AML: 48 nmol/L < Ler: 127 nmol/L) in right atrial trabeculae. 3. The vasorelaxant potency of LER (IC50 0.5 nmol/L) and AML (IC50 0.8 nmol/L) was similar and significantly increased compared with that of NIF (IC50 5.9 nmol/L) in arteria mammaria preparations of the very same patients. 4. The following rank order was obtained for vasoselectivity: LER (260) < AML (60) < NIF (0.6). 5. The pharmacological effects of LER and AML were still present 2 h after drug washout. 3. Lercanidipine is characterized by a high vasoselectivity and a prolonged interaction with the L-type calcium channel in human cardiovascular tissue This may be advantageous, especially in the treatment of patients with arterial hypertension.

Adolescent↗

PubMed2004

Mechanisms of beta 3-adrenoceptor-induced eNOS activation in right atrial and left ventricular human myocardium.

beta-Adrenoceptors are important modulators of cardiac function. The present study investigated beta(3)-adrenergic eNOS activation in human myocardium. We measured nitric oxide (NO) liberation (diaminofluorescence) and signal transduction (immunohistochemistry, phosphorylation of eNOS(Ser1177), eNOS(Thr495), eNOS(Ser114), Akt/protein kinase B (Akt/PKB), and eNOS translocation) in human right atrial (RA, aortocoronary-bypass OP) and left ventricular nonfailing (LV, rejected donor hearts) myocardium after application of BRL 37344 (BRL), a preferential beta(3)-adrenoceptor agonist. In both RA and LV, BRL (10 microl) induced a liberation of NO. An eNOS activation via translocation was only observed in RA after application of BRL (10 microM). Yet, the NO liberation in both LV and RA was accompanied by phosphorylation of eNOS(Ser1177) and Akt/PKB. BRL-induced eNOS phosphorylation was abolished by LY292004, a blocker of PI-3 kinase. eNOS-Ser(114) phosphorylation was unchanged in RA, but decreased in LV after beta(3)-adrenergic stimulation. BRL did not alter phosphorylation of eNOS(Thr495). In conclusion, receptor-dependent eNOS activation is differentially regulated in the human heart. In the left ventricle, eNOS activation via phosphorylation seems to be of major importance, whereas in human atrial myocardium eNOS translocation is the predominant mechanism induced by beta(3)-adrenergic activation.

Adrenergic beta-3 Receptor Agonists↗

PubMed2004

Na+/Ca2+ exchanger overexpression impairs frequency- and ouabain-dependent cell shortening in adult rat cardiomyocytes.

The Na(+)/Ca(2+) exchanger (NCX) may influence cardiac function depending on its predominant mode of action, forward mode or reverse mode, during the contraction-relaxation cycle. The intracellular Na(+) concentration ([Na(+)](i)) and the duration of the action potential as well as the level of NCX protein expression regulate the mode of action of NCX. [Na(+)](i) and NCX expression have been reported to be increased in human heart failure. Nevertheless, the consequences of altered NCX expression in heart failure are still a matter of discussion. We aimed to characterize the influence of NCX expression on intracellular Ca(2+) transport in rat cardiomyocytes by adenoviral-mediated gene transfer. A five- to ninefold (dose dependent) overexpression of NCX protein was achieved after 48 h by somatic gene transfer (Ad.NCX.GFP) versus control (Ad.GFP). NCX activity, determined by Na(+) gradient-dependent (45)Ca(2+)-uptake, was significantly increased. The protein expressions of sarco(endo)plasmic reticulum Ca(2+)-ATPase, phospholamban, and calsequestrin were unaffected by NCX overexpression. Fractional shortening (FS) of isolated cardiomyocytes was significantly increased at low stimulation rates in Ad.NCX.GFP. After a step-wise enhancing frequency of stimulation to 3.0 Hz, FS remained unaffected in Ad.GFP cells but declined in Ad.NCX.GFP cells. The positive inotropic effect of the cardiac glycoside ouabain was less effective in Ad.NCX.GFP cells, whereas the positive inotropic effect of beta-adrenergic stimulation remained unchanged. In conclusion, NCX overexpression results in a reduced cell shortening at higher stimulation frequencies as well as after inhibition of sarcolemmal Na(+)-K(+)-ATPase, i.e., in conditions with enhanced [Na(+)](i). At low stimulation rates, increased NCX expression enhances both intracellular systolic Ca(2+) and contraction amplitude.

Adenoviridae↗

PubMed2004

Ouabain increases myofibrillar Ca2+ sensitivity but does not influence the Ca2+ release in human skinned fibres.

The present study investigated the impact of the Na(+) pump inhibitor ouabain (g-strophanthin) on Ca(2+) sensitivity and Ca(2+) release in human right auricular trabeculae (coronary bypass) and in skinned muscle fibres from left ventricular myocardium (cardiac transplantation, dilated cardiomyopathy). A time-dependent increase in force of contraction was observed in right auricular trabeculae in response to ouabain (100 nM) before the intracellular Ca(2+) transient (fura-2) increased (n=6). In triton X-skinned fibres (no sarcoplasmic reticulum) of human failing myocardium, ouabain (1-100 nM) concentration-dependently increased tension at a free extracellular Ca(2+) concentration of 1 microM and the Hill coefficient of the Ca(2+)-dependent tension development. Ouabain (1-100 nM) did not directly induce a Ca(2+) release out of the sarcoplasmic reticulum, nor did it alter the caffeine (10 mM) induced sarcoplasmic reticulum Ca(2+) release in saponin-skinned fibre preparations in which the sarcoplasmic reticulum had been Ca(2+)-loaded. In conclusion, ouabain increases myofibrillar Ca(2+) sensitivity possibly due to an increase in the cooperativity of the thick and thin myofilaments. This mechanism may additionally contribute to the positive inotropic effect of ouabain.

Adult↗

PubMed2003

Ser16-, but not Thr17-phosphorylation of phospholamban influences frequency-dependent force generation in human myocardium.

Beta-adrenoceptor/cAMP-dependent Ser16-phosphorylation as well as Ca(2+)-dependent Thr17-phosphorylation of phospholamban (PLB) influences SERCA 2a activity and thus myocardial contractility. To determine the cross-signaling between Ca2+ and cAMP pathways, the phosphorylation of Ser16-PLB and Thr17-PLB was studied at increasing stimulation frequencies as well as in the presence of beta-adrenergic stimulation in isolated ventricular trabeculae from failing (dilative cardiomyopathy, DCM, heart transplants, n=9) and non-failing human myocardium (donor hearts, NF, n=9). In addition, we measured the intracellular Ca(2+)-transient (fura-2) at increasing stimulation frequencies (0.5-3.0 Hz). Protein expression of SERCA 2a and phospholamban was similar in DCM and NF. In DCM, diastolic [Ca2+]i was increased and systolic [Ca2+]i as well as Ser16 PLB-phosphorylation were decreased as compared to NF at 0.5 Hz. The positive force-frequency relationship in human non-failing myocardium was accompanied by a frequency-dependent increase in Ser16-PLB, but not Thr17-PLB phosphorylation. In DCM, Ser16-PLB as well as Thr17-PLB phosphorylation were not altered at higher stimulation frequencies. After application of isoprenaline (1 microM), a profound increase in Ser16-PLB phosphorylation was accompanied by a small increase in Thr17-PLB phosphorylation, only in NF. The frequency-dependent phosphorylation of Ser16-PLB may favor an increase in Ca2+ transient and force generation in humans. Cross talk signaling of Ser16/Thr17-PLB phosphorylation after beta-adrenergic stimulation exists in non-failing, but not in failing human myocardium. The Ca(2+)-dependent CaM-kinase activity may be altered in human heart failure.

Adrenergic beta-Agonists↗

PubMed2003

Lack of inverse agonistic activity of nebivolol, its D- and L-enantiomers and of in vivo metabolized nebivolol in human myocardium.

The pharmacological profile of nebivolol may be mediated by its enantiomers and/or its hydroxylated metabolites. Therefore, the cardiac effects of the nebivolol enantiomers as well as of serum specimens containing hydroxylated nebivolol metabolites were studied in human myocardium. For control, the beta1-adrenoceptor selective antagonist metoprolol was used. After pre-stimulation of force of contraction with forskolin (0.3 microM) or isoprenaline (0.01 microM), force developement was decreased only at high concentrations (> or =300 nM) of nebivolol or its enantiomers in isolated trabeculae. Nebivolol and its enantiomers, in contrast to metoprolol (0.4 microM: -72% basal force), produced only minor negative intropic effects in isolated trabeculae under basal conditions. Basal force of contraction was not decreased by in vivo metabolized nebivolol in pharmacological concentrations. Neither D- nor L-nebivolol (30 microM) influenced myofibrillar Ca2+ responsiveness. Nebivolol and the D-enantiomer, but not the L-enantiomer (all 0.5 microM), improved the frequency-dependent force generation. D-Nebivolol, in contrast to L-nebivolol, was a beta1-adrenoceptor selective compound in membrane preparations from non-failing donor hearts. In conclusion, nebivolol and its enantiomers as well as in vivo metabolized nebivolol produce only minor negative inotropic effects. This and the finding that nebivolol and its D-enantiomer improve the frequency-dependent force generation may be of particular advantage when treating patients with already compromised cardiac function.

Adenylyl Cyclases↗

PubMed2003

Reduced length-dependent cross-bridge recruitment in skinned fiber preparations of human failing myocardium.

A depressed activity of myosin ATPase has been described in human failing myocardium. Since alterations in cross-bridge kinetics may affect both systolic and diastolic cardiac function, the present study simultaneously investigated Ca(2+)-dependent tension and actomyosin ATPase activity (MYO) in triton X-skinned fiber preparations of human non-failing (donor hearts, n=8) and failing (dilated cardiomyopathy, n=11) left ventricular myocardium at increasing sarcomeric length (1.9 and 2.1 microm, alpha-actinin staining). The MYO/tension ratio was analyzed as a parameter characterizing myofibrillar energetics. At a sarcomere length of 1.9 microm, the Ca(2+) sensitivity of tension was significantly increased in human failing compared to non-failing myocardium. In human non-failing myocardium, maximal Ca(2+)-activated tension [1.9 microm vs. 2.1 microm, 23.7 (1.9) vs. 28.3 (1.9) mN/mm(2)] and the Ca(2+) sensitivity of tension [EC(50)Ca(2+ )(pCa): 5.67 (0.06) vs. 7.07 (0.11)] were increased by increasing sarcomere length. This was accompanied by an enhancement in Ca(2+)-dependent MYO [+72 (11) vs. +101 (9) microM ADP/s] as well as an increase in the Ca(2+)-sensitivity of MYO [EC(50)Ca(2+ )(pCa): 5.84 (0.08) vs. 6.86 (0.08)]. In human failing myocardium, only Ca(2+) sensitivity of tension (but not of MYO) increased. Tension cost was increased in failing vs. non-failing tissue [1.9 microm: 4.18 (0.06) vs. 3.53 (0.06) (mN.s)/(mm(2). microM ADP); 2.1 microm: 4.28 (0.13) vs. 3.52 (0.05) (mN.s)/(mm(2). microM ADP)]. We concluded that, in human failing myocardium, the length-dependent force generation may be blunted due to an already increased Ca(2+) affinity of troponin C as well as an impairment of length-dependent cross-bridge recruitment.

Adult↗

PubMed2003

Beta 1-adrenoceptor selectivity of nebivolol and bisoprolol. A comparison of [3H]CGP 12.177 and [125I]iodocyanopindolol binding studies.

There is an ongoing discussion on whether or not high beta(1)-adrenoceptor selectivity of beta-adrenoceptor antagonists may be favorable in the treatment of patients with heart failure. The present study compared the beta(1)-adrenoceptor selectivity of nebivolol and bisoprolol with that of carvedilol in the human myocardium, using a binding assay in conjunction with either the hydrophilic ligand (+/-)-[3H]4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzimidazole-2-on HCl ([3H]CGP 12.177) or the lipophilic ligand [125I]iodocyanopindolol as radiolabeled compound. Measurements were made using membrane preparations obtained from identical nonfailing donor hearts. beta-adrenoceptor density was found to be slightly higher when [125I]iodocyanopindolol was used compared to [3H]CGP 12.177 (256+/-15 and 213+/-18 fmol/mg protein, respectively). When the highly beta(1)-adrenoceptor-selective compound 2-hydroxy-5-(2-(hydroxy-3-(4((1-methyl-4-trifluoromethyl)-1-H-imidazol-2-yl)-phenoxy)-propyl)-aminoethoxyl)-benzamide (CGP 20.712A) and the highly beta(2)-adrenoceptor-selective compound erythro-(+/-)-1-(7-methylindan-4-yloyl)-3-isopropylaminobutan-2-ol HCl (ICI 118.551) were used in competition experiments, a similar proportion of beta(1)-adrenoceptors was seen for [3H]CGP 12.177 (69.3+/-1.6%) and for [125I]iodocyanopindolol (67.0+/-2.1%). K(i)(beta(1)) and K(i)(beta(2)) were obtained in the presence of 50 nM ICI 118.551 and 300 nM CGP 20.712A. The rank order of beta(1)-adrenoceptor selectivity (K(i)(beta(2))/K(i)(beta(1)) ratio) was nebivolol (for [3H]CGP 12.177 46.1 and for [125I]iodocyanopindolol 22.5)>bisoprolol (13.1 and 6.4)>carvedilol (0.65 and 0.41). To investigate whether in vivo metabolized nebivolol retains high beta(1)-adrenoceptor selectivity, serum specimens were collected before and 2 h after oral administration of 5 mg nebivolol. The samples were used for [125I]iodocyanopindolol binding studies with the myocardial membrane preparations. In these samples, the binding of [125I]iodocyanopindolol to beta(1)-adrenoceptors was inhibited by 46.4+/-5.3%, whereas the binding to beta(2)-adrenoceptors was inhibited by 20.5+/-1.1% compared to that of control samples. It is concluded that nebivolol is approximately 3.5 times more beta(1)-adrenoceptor-selective than bisoprolol in the human myocardium. Furthermore, in vivo metabolized nebivolol retains beta(1)-adrenoceptor selectivity.

Adrenergic beta-1 Receptor Antagonists↗

PubMed2003

Longer term effects of ouabain on the contractility of rat isolated cardiomyocytes and on the expression of Ca and Na regulating proteins.

Cardiac glycosides like ouabain are used in the therapy of heart failure and atrial fibrillation. They exert a positive inotropic effect on cardiomyocytes by inhibiting the plasma membrane sodium pump (Na,K-ATPase), decreasing the Ca-extrusion by the sarcolemmal cardiac sodium/calcium exchanger (NCX) and increasing the intracellular Ca-concentration and Ca-release during subsequent contraction cycles.The longer term effects of ouabain treatment on the expression of proteins important for Ca- and Na-homeostasis are not well known and were investigated in this study. Isolated adult rat cardiomyocytes were cultured in the presence or absence of ouabain (30 microM). In these cells, the expression of the Na,K-ATPase, Na,Ca-exchanger (NCX), the sarcoplasmic reticulum Ca-ATPase (SERCA 2a) and phospholamban (PLB) were studied by Western blot. In addition, the contractile function of these cells was studied after electrical stimulation. After 2 days of ouabain treatment immunoreactivity of the NCX was increased significantly relative to control which was set 1 (1.78 +/- 0.16 vs. 1 +/- 0.13; n = 8; P = 0.003) and at day 4 (1.96 +/- 0.35 vs. 1 +/- 0.20; n = 6; P = 0.02). All other proteins (SERCA 2a, PLB and Na,K-ATPase a1 and b1) remained unchanged (n >/= 4). Ouabain treatment increased the fractional shortening of isolated cardiomyocytes at day 0 (1 Hz: 9.64 +/- 0.73 %, n = 24, vs. 7.18 +/- 0.60 %; n = 21; P = 0.01), whereas at day 2 the contractility was unchanged (1 Hz: 7.23 +/- 1.08 %, n = 9 vs. 7.70 +/- 0.63 %; n = 10, P = 0.71). The inhibition of SERCA 2a (10 microM cyclopiazonic acid (CPA)) decreased contractility in both the ouabain treated group and in controls, at day 0 and at day 2. These results show that chronic ouabain treatment increases the protein expression of the NCX. The positive inotropic effect of ouabain can no longer be observed after a chronic treatment for 2 days. Thus, both protein expression and contractile function of the cells are specifically altered by longer term cardiac glycoside exposure. Whether such regulation can be found in human cardiomyocytes and the resulting consequences in the clinical setting remain to be determined.

Animals↗

PubMed2002

Modulation of SERCA: implications for the failing human heart.

Human heart failure is characterized by distinct alterations in the intracellular homeostasis and key regulators of the sarcoplasmic reticulum Ca2+ sequestration mechanisms. Systolic peak Ca2+ is reduced, diastolic Ca2+ levels are increased and diastolic Ca2+ decay is prolonged. Recently specific changes in the expression, function and modulation of SR Ca2+-ATPase (SERCA) have been elucidated. As such, in a variety of studies SERCA expression appeared to be decreased in the failing human heart, although these findings have been discussed controversially depending on the studied tissue, especially with respect to the non-failing samples and regional variation in the obtained samples. However, consistent findings of a diminished Ca2+ dependent SERCA activation were found. Increasing evidence has been provided that one of the underlying mechanisms for a decreased activation of SERCA is its altered regulation. With respect to this, the modulations through phospholamban and Ca2+-dependent protein kinase II (CaMK II) play a detrimental role in regulating SERCA function. Phospholamban phosphorylation of SERCA at the serine-16 and threonine-17 site is diminished in human heart failure resulting in decreases in the apparent affinity for Ca2+ of the SR Ca2+ uptake rates. In contrast, activation of CaMK II leads to an increased maximal velocity of SR Ca2+ sequestration that may enhance SR Ca2+-load. Additional regulation has been recently elucidated by changes in the apparent coupling ratio of Ca2+ transported per ATP hydrolysed. This review summarizes recent advances in the understanding how SERCA is modulated under physiological and pathophysiological conditions.

Animals↗

PubMed2002

Increased Ca2+-sensitivity of myofibrillar tension in heart failure and its functional implication.

In human failing myocardium, an increased Ca2+-sensitivity of myofilament tension development has been described in Triton X skinned cardiac myocytes compared to cardiomyocytes obtained from non-failing human donor hearts. The present study aimed to investigate whether there are functional implications of the increased Ca2+-sensitivity in heart failure and whether alterations of myofilament function are already obvious at earlier stages of heart failure, such as in cardiac hypertrophy or whether alterations of the intracellular Ca2+-homeostasis are able to induce alterations in myofilament function. Ca2+-activated tension development was measured in Triton X-skinned fibers from human failing and non-failing myocardium. Ca2+-sensitivity of myofilament tension development was significantly shifted to the left in human failing myocardium. Plots of diastolic free Ca2+ versus diastolic tension development showed that in a range of similar diastolic Ca2+-concentrations, diastolic tension was significantly enhanced in the failing hearts. The Ca2+/tension relationship was shifted to the right in Triton X-skinned fiber preparations from transgenic renin overexpressing rats (TG(mREN2)27), shown to have concentric hypertrophy. In addition, the Ca2+/tension relationship was unchanged in phospholamban knock-out mice with an increased systolic Ca2+ (and enhanced diastolic Ca2+-load). It is concluded that the increased Ca2+-sensitivity of myofilament tension observed in single cardiomyocytes from failing human myocardium may be a phenomenon also present in multicellular preparations and may contribute to the diastolic dysfunction observed in human heart failure. Alterations of myofilament function occur at very early stages of heart failure and may be species dependent, or dependent on intracellular free Ca2+-levels.

Animals↗

PubMed2002

Isometric force kinetics upon rapid activation and relaxation of mouse, guinea pig and human heart muscle studied on the subcellular myofibrillar level.

The kinetics of force development and relaxation upon rapid application and removal of Ca2+ was measured in bundles of few myofibrils isolated from triton X-100 skinned left ventricular trabeculae of mice (M), guinea pigs (G) and humans (H). Upon rapidly switching from relaxing solution (pCa 7.5) to activating solution (pCa 4.5) at 10 degrees C, force rose by a single exponential with a rate constant k(act) of 5.2 s(-1) (M), 1.7 s(-1) (G) and 0.3 s(-1) (H) to a plateau of 0.14 microN/microm2 (M), 0.16 microN/microm2 (G) and 0.15 microN/microm2 (H). A rapid release followed by a rapid restretch to the original length applied during steady-state Ca2+ activation at pCa 4.5 induced an exponential force redevelopment with a rate constant k(redev) that was indistinguishable from k(act), indicating that k(act) is limited by cross-bridge turnover kinetics rather than by the Ca2+-induced activation of the regulatory system. Upon rapidly switching from pCa 4.5 to pCa 7.5, force decayed in a pronounced biphasic manner. Thus a slow initial, almost linear decay with a rate constant k(lin) of 1.8 s(-1) (M), 0.6 s(-1) (G) and 0.15 s(-1) (H) and a duration t(lin) of 0.06 s (M), 0.11 s (G) and 0.3 s (H) was followed by a rapid exponential decay with a rate constant k(rel) of 18 s(-1) (M), 11 s(-1) (G) and 4.6 s(-1) (H). The pronounced biphasic shapes of the force decays determined here for the first time in cardiac myofibrils differs from the force decays that had been reported for multicellular skinned trabeculae in which relaxation was induced by rapid removal of Ca2+ by flash photolysis of caged Ca2+ chelators. In the skinned trabeculae, no pronounced initial slow phase was observed. The force decays shown here are much more similar to those reported for single skeletal myofibrils. The kinetics of isometric relaxation of skinned trabeculae (i.e., multicellular preparations), therefore, do not reflect the kinetics of force relaxation at the cardiac myofibrillar level.

Animals↗

PubMed2002

Bucindolol exerts agonistic activity on the propranolol-insensitive state of beta1-adrenoceptors in human myocardium.

In congestive heart failure patients, treatment with beta-adrenoceptor antagonists improves symptoms and decreases mortality. However, intrinsic sympathomimetic activity of beta-adrenoceptor antagonists might be disadvantageous in chronic heart failure. The nonselective beta1- and beta2-adrenoceptor antagonist bucindolol has failed to decrease mortality in clinical trials. A putative beta4-adrenoceptor, which mediates positive inotropic effects by activation of the adenylate cyclase has been described. Recently, this putative beta4-adrenoceptor has been identified to be a propranolol-insensitive state of the beta1-adrenoceptor. The present study aimed to characterize whether bucindolol exhibits agonistic activity on this atypical beta1-adrenoceptor state as one possible reason for clinical inefficiency. For comparison (S)-4-(3'-t-butylamino-1'-hydroxypropoxy)-benzimidozole-2 (CGP 12177), metoprolol, and nebivolol were investigated. Bucindolol did not reveal intrinsic sympathomimetic activity in electrically driven (1 Hz, 37 degrees C), forskolin-stimulated, left ventricular papillary muscle strips (donor hearts, nonfailing; n = 5) and in right auricular trabeculae (bypass operation; n = 4). Functional studies on the propranolol-insensitive state of beta1-adrenoceptors were performed in isolated muscle preparations after beta1- and beta2-adrenoceptor antagonism (propranolol, 1 microM), inhibition of beta3-mediated inotropic effects (N-nitro-L-arginine, 100 microM) and forskolin treatment (0.3 microM). Positive inotropic response to stimulation of atypical state beta1-adrenoceptors could be demonstrated in right auricular as well as left ventricular human myocardium (CGP 12177 treatment, 10 microM). Under these conditions, also bucindolol, but not metoprolol and nebivolol, significantly increased contractility (all 10 microM). In conclusion, bucindolol but not metoprolol or nebivolol mediate positive inotropic effects in human myocardium due to activation of atypical state beta1-adrenoceptors. Thus, the agonistic activity of bucindolol may influence outcome in heart failure patients.

Adrenergic beta-Agonists↗

PubMed2002

Beneficial effects of the Ca(2+) sensitizer levosimendan in human myocardium.

Levosimendan has been reported to increase cardiac Ca(2+) sensitivity, thereby not enhancing intracellular Ca(2+) or diastolic tension. This may be advantageous for the treatment of heart failure patients. Therefore, the present study investigates the mode of action of levosimendan in both failing and nonfailing (NF) human myocardium. The effects of levosimendan on contractile force, Ca(2+) transient (fura 2), and the force-frequency relationship (0.5-3 Hz) were studied in left ventricular terminally failing [dilated cardiomyopathy (DCM; n = 18)] and nonfailing (NF) myocardium (donor hearts, n = 6). Levosimendan (0.03-10 micromol/l) increased contractile force in NF (EC(50): 0.38 micromol/l). In left ventricular failing myocardium, levosimendan only increased force after prestimulation with isoprenaline (0.1 micromol/l, EC(50) levosimendan: 0.062 micromol/l) or after elevation of the extracellular Ca(2+) concentration from 1.8 to 3.2 mmol/l. After application of isoprenaline, levosimendan shortened relaxation and contraction kinetics. Levosimendan did not change the systolic Ca(2+) transient but it improved the force-frequency relationship in DCM. In conclusion, levosimendan improves contraction in failing human myocardium under conditions with already increased intracellular Ca(2+).

Calcium↗