Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan

Haikala, Heimo; Kaivola, Juha; Nissinen, Erkki; Wall, Pv̈i; Levijoki, Jouko; Lindén, Inge‐Britt

doi:10.1016/0022-2828(95)90009-8

Cited by 278 publications

(189 citation statements)

References 23 publications

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“…L evosimendan (Levo) is a myocardial calcium sensitizer 1,2 and vasodilator 3,4 that is being evaluated for the shortterm treatment of patients with decompensated heart failure. [5][6][7][8] Although Levo has an elimination half-life of Ϸ1 hour, its active metabolite, OR-1896, has a much longer elimination half-life of Ϸ70 to 80 hours.…”

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confidence: 99%

Sustained Hemodynamic Effects of Intravenous Levosimendan

2003

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Background-The short-term infusion of levosimendan (Levo) improves hemodynamic function in patients with decompensated heart failure. The metabolites of Levo have a prolonged half-life, and one is hemodynamically active. The goal of this study was to determine whether the hemodynamic effects of Levo are sustained during a long-term infusion and beyond the discontinuation of drug infusion. Methods and Results-Patients with decompensated heart failure received escalating infusion rates of intravenous Levo (nϭ98) or placebo (nϭ48) for 6 hours. At the end of 6 hours, 85 of the Levo-treated patients were continued on open-label drug for a total of 24 hours, at which time they were randomized 1:1 to an additional 24 hours of Levo (nϭ43) or placebo (nϭ42).The hemodynamic effects observed at 24 hours were maintained at 48 hours in both the continuation and withdrawal groups and did not differ between groups. Although the plasma concentration of Levo decreased rapidly in the withdrawal group, concentrations of the active metabolite OR-1896 were similar in the continuation and withdrawal groups at 24 hours and increased further (3.5-fold to 4-fold) and to a similar extent in both groups at 48 hours. Conclusions-The hemodynamic effects of Levo were maintained during a 48-hour continuous infusion and for at least 24 hours after discontinuation of a 24-hour infusion. The active metabolite OR-1896 increased for at least 24 hours after cessation of drug infusion and may account for the prolonged hemodynamic effects of Levo.

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confidence: 99%

Sustained Hemodynamic Effects of Intravenous Levosimendan

2003

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“…den de bu me ka niz ma nın so rum lu ol du ğu dü şü -nül mek te dir. [3][4][5][6] Bi li nen inot ro pik ajan la ra ve in traa or tik ba lon pom pa sı uy gu la ma la rı na ce vap alı na ma yan dü şük kalp de bi li ol gu lar da do za bağım lı ola rak kalp de bi si ve atım vo lü mün de ar tışa, pul mo ner ka pil ler uç ba sınç ve sis te mik vas kü ler re zis tans ta azal ma ya yol aç tı ğı bil di ril miş tir. 7 Le vo si men da nın kalp trans plan tas yo nun da kul la nı mı na da ir ye ter li bil gi bu lun ma mak ta dır.…”

Section: Ortotopik Kalp Transplantasyonundaunclassified

“…Be ra be rin de kul la nı lan di ğer inot rop la rın do zu nu dü şür mek te yar dım cı oldu ğu için ge li şe bi le cek yan et ki le ri ni azalt ma ko nusun da da fay da sağ la ya bil mek te dir. [3][4][5] Le vo si men dan da mar du va rın da ki düz kas hüc re le rin de ATP ba ğım lı K + ka nal la rı nın ak ti ve ede rek va zo di la tas yo na ne den olur. Ko ro ner ar terler de va zo di la tas yo na ne den ola rak mi yo kar di yal kan akı mı nı art tı rır.…”

Section: 2unclassified

“…Oluş tur du ğu pul mo ner ve siste mik va zo di la tas yon mi yo kar diy al ön ve ard yük -te azal ma ya yol açar. [3][4][5] Le vo si men dan atı lı mın dan ön ce ta ma men meta bo li ze olur, ak tif me ta bo li ti olan OR-1896'ya dö-nü şür. Le vo si men da nın ya rı lan ma öm rü bir sa at iken ak tif me ta bo li ti nin ya rı lan ma öm rü 75-80 saat tir.…”

Section: 2unclassified

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Levosimendan Treatment During Orthotopic Heart Transplantation: Case Report

Durak¹,

Yağar²,

Uzuner³

2010

Turkiye Klinikleri J Med Sci

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“…2,3 Thus this drug is recommended in acute and decompensated heart failure treatment thank to its with positive inotropic and anti-stunning effects mediated by calcium sensitization of the contractile proteins. 4,5 Besides increasing the strength of cardiac contractions, levosimendan induces coronary and peripheral vasodilatation through the opening of sarcolemmal ATP-dependent K + channels, 6,7 an effect reported also in rat atrial and ventricular myocytes. 8,9 Mitochondrial ATP-dependent K + channels in preparations of rat liver and heart are opened by levosimendan, as well.…”

mentioning

confidence: 97%

Positive Inotropic Effects of Levosimendan are Modulated by KATP Channels in Isolated Human Atrial Trabeculae

Usta¹,

Puddu²,

Papalia³

et al. 2010

Turkiye Klinikleri J Med Sci

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A AB BS S T TR RA AC CT T O Ob b j je ec c t ti i v ve e: : The aim of this study was to in ves ti ga te whet her po tas si um chan nel bloc king agents we re ab le to mo du la te po si ti ve inot ro pic ef fect of le vo si men dan in iso la ted hu man at rial tra be cu lar musc les or not. M Ma a t te e r ri i a al l a an nd d M Me et t h ho od ds s: : The right at ri al ap pen da ge samp les (1 cm 2 , 500-1000 mg) we re re mo ved and im mer sed in pre oxy ge na ted and mo di fi ed Tyro de's so lu ti on. Prepa ra ti ons we re used to in ves ti ga te the con cen tra ti on-ef fect re la ti on of le vo si men dan (10-9 to 10-4 M) alo ne or in the pre sen ce of Ca2+-de pen dent po tas si um chan nel bloc ker 4-ami nop yri di ne (4-AP: 500 µM), ATP-de pen dent po tas si um chan nel bloc ker gli benc la mi de (1 µM) or mi toc hon dri al ATP-de pen dent po tas si um chan nel bloc ker 5-hydroxy de ca no a te (5-HD: 300 µM) on per cent de ve lo ped ten si on (%DT). R Re e s su ul lt ts s: : Le vo si men dan pro du ced con cen tra ti on-de pen dent in cre ments in %DT. Both the sen si ti vity (pD2) and ma xi mum res pon se (Emax) of hu man at ri al tra be cu la e to levo si men dan (7.31 ± 0.02 and 29.2 ± 1.1 mN, res pec ti vely) sig ni fi cantly and similarly re du ced in pre sen ce of gli benc la mi de (5.83 ± 0.04 and 17.4 ± 1.61 mN) and 5-HD (6.14 ± 0.05 and 18.5 ± 3.1 mN). Ho we ver, 4-AP did not ca u se a sig ni fi cant al te ra ti on in sen si ti vity (pD2= 6.77 ± 0.05) or Emax (27.6 ± 2.0 mN) to le vo si men dan. C Co on nc c l lu u s si i o on n: : Both sar co lem mal and mi toc hon dri al ATP-de pen dent po tas si um chan nels are imp li ca ted to mo du la te po si ti ve inot ro pic ef fect of le vo si men dan in hu man at ri al tra be cu la e. K Ke ey y W Wo or rd ds s: : Simendan; potassium channels; cardiotonic agents Ö ÖZ ZE ET T A Am ma aç ç: : Bu ça lış ma nın ama cı izo le in san at ri yal tra be kü ler ka sın da po tas yum ka nal blo ke edici ajan la rın le vo si men da nın po zi tif inot ro pik et ki le ri ni mo dü le edip ede me di ği ni araş tır mak tır. G Ge e --r re eç ç v ve e Y Yö ön n t te em m l le er r: : Sağ at ri yal apen diks ör nek le ri (1 cm 2 , 500-1.000 mg) alın dı ve ön ce den ok si je ni ze edil miş mo di fi ye Tyro de so lüs yo nu na ko nu la rak or gan ban yo su na asıl dı. Le vo si men da nın kon santras yon-et ki iliş ki si tek ba şı na (10-9 ile 10-4 M), Ca2 -ba ğım lı po tas yum ka nal blo kö rü 4-ami no piri din (4-AP: 500 µM), ATP-ba ğım lı po tas yum ka nal blo kö rü gli benk la mid (1µM) ve ya mi to kon dri al ATP-ba ğım lı po tas yum ka nal blo kö rü 5-hid rok si de ko nat (5-HD: 300 µM) ile bir lik te olu şan ka sıl -ma gü cü araş tı rıl mak ama cıy la pre pa rat lar ha zır lan dı. B Bu ul l g gu u l la ar r: : Le vo si men dan % ka sıl ma gü cün de kon san tras yon-ba ğım lı ar tı şa ne den ol du. İnsan at ri yal tra be kü la sı nın le vo si men dan için hem sensi ti vi te si (PD2) hem de mak si mum ya nı tı (Emax), gli benk la mid (5.83 ± 0.04 ve 17.4 ± 1.61 mN) ve 5-HD...

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Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan

Cited by 278 publications

References 23 publications

Sustained Hemodynamic Effects of Intravenous Levosimendan

Sustained Hemodynamic Effects of Intravenous Levosimendan

Levosimendan Treatment During Orthotopic Heart Transplantation: Case Report

Positive Inotropic Effects of Levosimendan are Modulated by KATP Channels in Isolated Human Atrial Trabeculae

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