Article

A role for the RISK pathway and K(ATP) channels in pre- and post-conditioning induced by levosimendan in the isolated guinea pig heart.

Department of Biomedical Sciences, Faculty of Health Sciences, University of Stellenbosch, Western Cape, South Africa.
British Journal of Pharmacology (Impact Factor: 5.07). 05/2008; 154(1):41-50. DOI: 10.1038/bjp.2008.52
Source: PubMed

ABSTRACT Myocardial reperfusion injury prevents optimal salvage of the ischaemic myocardium, and adjunct therapy that would significantly reduce reperfusion injury is still lacking. We investigated whether (1) the heart could be pre- and/or post-conditioned using levosimendan (levosimendan pre-conditioning (LPC) and levosimendan post-conditioning (LPostC)) and (2) the prosurvival kinases and/or the sarcolemmal or mitochondrial K(ATP) channels are involved.
Isolated guinea pig hearts were treated with two 5 min cycles of levosimendan (0.1 microM) interspersed with vehicle perfusion, or two 5 min cycles of ischaemia/reperfusion, before coronary artery ligation (CAL) for 40 min at 36.5 degrees C. Hearts were treated with mitochondrial or sarcolemmal K(ATP) channel blockers before LPC or LPostC. For post-conditioning, hearts received three 30 s cycles of ischaemia/reperfusion or levosimendan/vehicle. Hearts were pretreated with levosimendan immediately before CAL (without washout). Cardiac function, infarct size and reperfusion injury salvage kinase activity was assessed.
LPC and LPostC halved the infarct size compared with controls (P<0.05). Treatment with K(ATP) channel blockers before LPC or LPostC reversed this decrease. Pretreating hearts with levosimendan increased activity of extracellular signal-regulated kinase (ERK) 42/44 on reperfusion and had the most marked infarct-lowering effect (P<0.05).
(1) Hearts could be pharmacologically pre- and post-conditioned with levosimendan; (2) levosimendan pretreatment is the most effective way to reduce infarct size, possibly by increasing ERK 42/44 activity; (3) benefits of LPC and LPostC were abolished by both K(ATP) channel blockers and (4) LPC may be useful before elective cardiac surgery, whereas LPostC may be used after acute coronary artery events.

0 Bookmarks
 · 
114 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Levosimendan is an inodilator indicated for the short-term treatment of acutely decompensated severe chronic heart failure, and in situations where conventional therapy is not considered adequate. The principal pharmacological effects of levosimendan are (a) increased cardiac contractility by calcium sensitisation of troponin C, (b) vasodilation, and (c) cardioprotection. These last two effects are related to the opening of sarcolemmal and mitochondrial potassium-ATP channels, respectively. Data from clinical trials indicate that levosimendan improves haemodynamics with no attendant significant increase in cardiac oxygen consumption and relieves symptoms of acute heart failure; these effects are not impaired or attenuated by the concomitant use of beta-blockers. Levosimendan also has favourable effects on neurohormone levels in heart failure patients. Levosimendan is generally well tolerated in acute heart failure patients: the most common adverse events encountered in this setting are hypotension, headache, atrial fibrillation, hypokalaemia and tachycardia. Levosimendan has also been studied in other therapeutic applications, particularly cardiac surgery - in which it has shown a range of beneficial haemodynamic and cardioprotective effects, and a favourable influence on clinical outcomes - and has been evaluated in repetitive dosing protocols in patients with advanced chronic heart failure. Levosimendan has shown preliminary positive effects in a range of conditions requiring inotropic support, including right ventricular failure, cardiogenic shock, septic shock, and Takotsubo cardiomyopathy.
    Heart, lung and vessels. 01/2013; 5(4):227-245.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute heart failure (AHF) emerges as a major and growing epidemiological concern with high morbidity and mortality rates. Current therapies in patients with AHF rely on two different strategies. Patients with hypotension, hypoperfusion or shock require inotropic support, while diuretics and vasodilators are recommended in patients with systemic or pulmonary congestion. Traditionally inotropic agents, referred to as Ca mobilizers load the cardiomyocyte with Ca and thereby increase oxygen consumption and risk for arrhythmias. These limitations of traditional inotropes may be avoided by sarcomere targeted agents. Direct activation of the cardiac sarcomere may be achieved by either sensitizing the cardiac myofilaments to Ca or activating directly the cardiac myosin. In this review we focus on sarcomere targeted inotropic agents, emphasizing their mechanisms of action and overview the most relevant clinical considerations.
    Journal of cardiovascular pharmacology 05/2014; · 2.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Since few studies have presented a thorough analysis of the effect of levosimendan (LEV) on contractility, our purpose was to investigate in vivo cardiac function as well as in vitro cardiomyocyte function and calcium (Ca(2+) ) handling following LEV treatment. Rats with post-myocardial infarction heart failure (HF) induced by ligation of the left anterior descending coronary artery and sham-operated animals were randomized to infusion of LEV (2.4 μg∙ kg(-1) ∙ min(-1) ) or vehicle for 40 min. Echocardiographic examination was coupled to pressure-volume sampling in the left ventricle before (B) and after (40 min) infusion. Isolated left ventricular cardiomyocytes were studied in an epifluorescence microscope. HF LEV (n=6), HF vehicle (n=7), sham LEV (n=5) and sham vehicle (n=6) animals were included. LEV infusion compared to vehicle in HF animals reduced left ventricular end-diastolic pressure and mean arterial pressure (both P<0.001) and improved the slope of the preload-recruitable stroke work (P<0.05). Administrating LEV to HF cardiomyocytes in vitro improved fractional shortening and Ca(2+) sensitivity index ratio, and increased the diastolic Ca(2+) (all P<0.01). In HF animals LEV improved the contractility by increasing the Ca(2+) sensitivity. Furthermore loading conditions were changed, and LEV could consequently change organ perfusion. An observed increase in diastolic Ca(2+) following LEV treatment and clinical implications of this should be further addressed. This article is protected by copyright. All rights reserved.
    Acta Physiologica 02/2014; · 4.38 Impact Factor

Full-text

Download
44 Downloads
Available from
May 27, 2014