Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium

被引:223
作者
Hasenfuss, G
Pieske, B
Castell, M
Kretschmann, B
Maier, LS
Just, H
机构
[1] Univ Gottingen, Zentrum Innere Med, Abt Kardiol & Pneumol, D-37075 Gottingen, Germany
[2] Univ Freiburg, Med Klin 3, Abt Kardiol & Angiol, D-7800 Freiburg, Germany
关键词
levosimendan; calcium; myocardium; heart failure;
D O I
10.1161/01.CIR.98.20.2141
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-Levosimendan was shown to increase calcium sensitivity by a novel mechanism and to inhibit phosphodiesterase III activity in animal myocardium. Methods and Results-We investigated the influence of levosimendan on isometric contractions and calcium transients (aequorin method) in muscle strips from human hearts with and-stage failing dilated or ischemic cardiomyopathy (n=27). Data were compared with the effects of the phosphodiesterase inhibitor milrinone (n=9). The average maximum increase in twitch tension was 47+/-14% (range, 6% to 150%) at a levosimendan concentration of 0.8+/-0.3 mu mol/L (P<0.01). This was associated with significant increases in maximum rates of tension rise and fall and decreases in times to peak tension, to 50% relaxation, and to 95% relaxation. In aequorin-loaded muscles, levosimendan 10(-6) mol/L increased average tension by 50% (P<0.02), associated with a nonsignificant increase in aequorin light (16%). With milrinone 10(-5) mol/L, average tension increased by 58% and aequorin light by 49% (P<0.05). In those muscle strips with pronounced inotropic effects (>50% increase in tension), there was a comparable and pronounced increase in aequorin light with both agents. However, in muscle strips with weak inotropic responses (<50% increase in tension), the increase in light was significantly higher with milrinone than with levosimendan. Conclusions-Levosimendan has inotropic and lusitropic actions in failing human myocardium. Comparison with the phosphodiesterase inhibitor milrinone indicates that in case of pronounced inotropic stimulation, the modes of action of the two agents may be similar (phosphodiesterase inhibition), whereas small inotropic effects of levosimendan may result predominantly from calcium sensitization.
引用
收藏
页码:2141 / 2147
页数:7
相关论文
共 25 条
  • [1] THE NOVEL CARDIOTONIC AGENT EMD-53-998 IS A POTENT CALCIUM SENSITIZER
    BEIER, N
    HARTING, J
    JONAS, R
    KLOCKOW, M
    LUES, I
    HAEUSLER, G
    [J]. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1991, 18 (01) : 17 - 27
  • [2] CONTRIBUTION OF CAMP-PHOSPHODIESTERASE INHIBITION AND SENSITIZATION OF THE CONTRACTILE PROTEINS FOR CALCIUM TO THE INOTROPIC EFFECT OF PIMOBENDAN IN THE FAILING HUMAN MYOCARDIUM
    BOHM, M
    MORANO, I
    PIESKE, B
    RUEGG, JC
    WANKERL, M
    ZIMMERMANN, R
    ERDMANN, E
    [J]. CIRCULATION RESEARCH, 1991, 68 (03) : 689 - 701
  • [3] EFFECT OF VASODILATOR THERAPY ON MORTALITY IN CHRONIC CONGESTIVE-HEART-FAILURE - RESULTS OF A VETERANS-ADMINISTRATION COOPERATIVE STUDY
    COHN, JN
    ARCHIBALD, DG
    ZIESCHE, S
    FRANCIOSA, JA
    HARSTON, WE
    TRISTANI, FE
    DUNKMAN, WB
    JACOBS, W
    FRANCIS, GS
    FLOHR, KH
    GOLDMAN, S
    COBB, FR
    SHAH, PM
    SAUNDERS, R
    FLETCHER, RD
    LOEB, HS
    HUGHES, VC
    BAKER, B
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1986, 314 (24) : 1547 - 1552
  • [4] 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
    EDES, I
    KISS, E
    KITADA, Y
    POWERS, FM
    PAPP, JG
    KRANIAS, EG
    SOLARO, RJ
    [J]. CIRCULATION RESEARCH, 1995, 77 (01) : 107 - 113
  • [5] EFFECTS OF VESNARINONE ON MORBIDITY AND MORTALITY IN PATIENTS WITH HEART-FAILURE
    FELDMAN, AM
    BRISTOW, MR
    PARMLEY, WW
    CARSON, PE
    PEPINE, CJ
    GILBERT, EM
    STROBECK, JE
    HENDRIX, GH
    POWERS, ER
    BAIN, RP
    WHITE, BG
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1993, 329 (03) : 149 - 155
  • [6] Mechanisms of action of calcium-sensitizing drugs
    Haikala, H
    Linden, IB
    [J]. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1995, 26 : S10 - S19
  • [7] TROPONIN C-MEDIATED CALCIUM SENSITIZATION INDUCED BY LEVOSIMENDAN DOES NOT IMPAIR RELAXATION
    HAIKALA, H
    NISSINEN, E
    ETEMADZADEH, E
    LEVIJOKI, J
    LINDEN, IB
    [J]. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1995, 25 (05) : 794 - 801
  • [8] CARDIAC TROPONIN-C AS A TARGET PROTEIN FOR A NOVEL CALCIUM SENSITIZING DRUG, LEVOSIMENDAN
    HAIKALA, H
    KAIVOLA, J
    NISSINEN, E
    WALL, P
    LEVIJOKI, J
    LINDEN, IB
    [J]. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1995, 27 (09) : 1859 - 1866
  • [9] TROPONIN C-MEDIATED CALCIUM SENSITIZATION BY LEVOSIMENDAN ACCELERATES THE PROPORTIONAL DEVELOPMENT OF ISOMETRIC TENSION
    HAIKALA, H
    LEVIJOKI, J
    LINDEN, IB
    [J]. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1995, 27 (10) : 2155 - 2165
  • [10] CALCIUM-SENSITIZING INOTROPIC AGENTS IN THE TREATMENT OF HEART-FAILURE - A CRITICAL-VIEW
    HAJJAR, RJ
    GWATHMEY, JK
    [J]. CARDIOVASCULAR DRUGS AND THERAPY, 1991, 5 (06) : 961 - 966