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Anesth Analg 2000;90:5
© 2000 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Levosimendan, a New Positive Inotropic Drug, Decreases Myocardial Infarct Size via Activation of KATP Channels

Judy R. Kersten, MD*, Matthew W. Montgomery, BS*, Paul S. Pagel, MD, PhD*,{dagger},§, and David C. Warltier, MD, PhD*,{dagger},{ddagger},§

Departments of *Anesthesiology, {dagger}Pharmacology, and {ddagger}Medicine (Division of Cardiovascular Diseases), Medical College of Wisconsin; and §Zablocki Veterans’ Affairs Medical Center, Milwaukee, Wisconsin

Address correspondence and reprint requests to Judy R. Kersten, MD, Medical College of Wisconsin, MEB-Room 462C, 8701 Watertown Plank Rd., Milwaukee, WI 53226.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We tested the hypothesis that levosimendan, a new positive inotropic drug that activates adenosine triphosphate-regulated potassium (KATP) channels in vitro, decreases myocardial infarct size in vivo. Myocardial infarct size was measured after a 60-min left anterior descending coronary artery occlusion and 3 h of reperfusion in dogs receiving either IV vehicle (0.9% saline) or levosimendan (24 µg/kg bolus followed by an infusion of 0.4 µg · kg-1 · min-1) in the presence or absence of glyburide (a KATP channel antagonist) pretreatment (100 µg/kg). Levosimendan increased (P < 0.05) the maximal rate of increase of left ventricular pressure and decreased myocardial infarct size from 24% ± 2% (control experiments) to 11% ± 2% of the left ventricular area at risk for infarction. Glyburide did not alter the hemodynamic effects of levosimendan but blocked levosimendan-induced reductions of infarct size. Subendocardial collateral blood flow was similar among groups. However, levosimendan increased subepicardial and midmyocardial collateral perfusion in the absence, but not in the presence, of glyburide. Levosimendan exerts cardioprotective effects via activation of KATP channels at a dose that simultaneously enhances myocardial contractility.

Implications: Levosimendan may be advantageous in patients requiring inotropic support who are also at risk of myocardial ischemia. Activation of adenosine triphosphate-regulated potassium channels during infusion of levosimendan may produce cardioprotective effects while simultaneously enhancing ventricular contractile function.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The myofilament calcium (Ca2+) sensitizer levosimendan is a new positive inotropic drug that enhances myocardial contractility in stunned myocardium (1), improves indices of diastolic function, and produces favorable hemodynamic alterations in humans with normal (2) and abnormal ventricular function (3). Similar to other drugs in the myofilament Ca2+ sensitizer class, levosimendan (0.03 to 10 µM) augments contractility by binding to Troponin C and stabilizing the Ca2+-bound conformation of this regulatory protein without directly affecting actin-myosin interaction (4). Recently, levosimendan (10 µM) has also been shown to activate adenosine triphosphate-regulated potassium (KATP) channels in arterial (5) and ventricular (6) myocytes. A positive inotropic agent that also activates KATP channels may be particularly advantageous in patients at risk of myocardial ischemia during treatment of cardiogenic shock, evolving myocardial infarction, or emergence from cardiopulmonary bypass (7). KATP-channel activation is an important mediator of ischemic preconditioning (8), and stimulation of KATP channels decreases myocardial infarct size IF (9) and enhances recovery of stunned myocardium (10). We tested the hypothesis that levosimendan decreases (IF) in vivo by activating KATP channels at a dose that also produces positive inotropic effects.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Medical College of Wisconsin. Furthermore, all conformed to the Guiding Principles in the Care and Use of Animals of the American Physiologic Society and were in accordance with the Guide for the Care and Use of Laboratory Animals (Washington, DC: National Academy Press, 1996).

As previously described (11), open-chest mongrel dogs (n = 38) were anesthetized with sodium barbital (200 mg/kg) and sodium pentobarbital (15 mg/kg). Additional anesthetics were administered as required, and fluid deficits were replaced with IV saline (0.9%) at 3 mL · kg-1 · hr-1. After tracheal intubation, the dogs were ventilated via positive pressure with oxygen enriched air (fraction of inspired oxygen = 0.25) to maintain arterial blood gas tensions within a physiological range. A double, pressure-transducer-tipped catheter was inserted into the aorta and left ventricle for measurement of aortic and left ventricular pressures and the maximal rate of increase of left ventricular pressure (dP/dtmax). Catheters were inserted into the left atrial appendage and the right femoral artery for the administration of radioactive microspheres and withdrawal of reference blood samples, respectively. A silk ligature was placed around the left anterior descending coronary artery (LAD), immediately distal to the first diagonal branch for production of coronary artery occlusion and reperfusion. Hemodynamics were continuously monitored on a polygraph during experimentation and digitized via a computer interfaced with an analog-to-digital converter.

Baseline systemic hemodynamic values were recorded 90 min after instrumentation was completed and calibrated. Dogs were randomly assigned to one of four experimental groups (Figure 1). In control experiments, dogs received IV vehicle (0.9% saline). The actions of levosimendan (24 µg/kg IV bolus followed by an infusion of 0.4 µg · kg-1 · min-1 beginning 15 min before coronary artery occlusion and discontinued at the onset of reperfusion) (7,12,13) on hemodynamics and IF were studied in a second group of dogs. The mechanism of the cardioprotective action of levosimendan was evaluated in two additional groups of dogs pretreated 30 min before coronary artery occlusion with the KATP channel antagonist glyburide (100 µg/kg IV) in the presence and absence of levosimendan. All dogs were subjected to a 60-min LAD occlusion and 3 h of reperfusion. Regional myocardial blood flow was determined with radioactive microspheres before coronary artery occlusion (e.g., during drug or vehicle administration), 30 min after the onset of LAD occlusion, and at 1 h of reperfusion.



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  		Figure 1. Schematic illustration of the experimental protocol. LEVO = levosimendan, GLB = glyburide.

 
Carbonized plastic microspheres (15 ± 2 µ [SD] in diameter) labeled with 141Ce, 103Ru, or 95Nb were used to measure regional myocardial perfusion. Microspheres were administered into the left atrium as a bolus for a 10-s period and flushed in with 10 mL of warm saline. A few seconds before the microsphere injection, a timed collection of reference arterial flow was started from the femoral arterial catheter and withdrawn at a constant rate of 7 mL/min for 3 min. Transmural tissue samples were selected from the normal (left circumflex coronary artery perfused) and previously ischemic (distal to the LAD occlusion and reperfusion) regions and were subdivided into subepicardial, midmyocardial, and subendocardial layers of approximately equal thickness. Samples were weighed and placed in scintillation vials, and the activity of each isotope was determined. Similarly, the activity of each isotope in the reference blood flow sample was assessed. Tissue blood flow (mL · min-1 · g-1) was calculated as Qr · Cm/Cr, where Qr = rate of withdrawal of the reference blood flow sample (mL/min), Cm = activity (cpm/g) of the myocardial tissue sample, and Cr = activity (cpm) of the reference blood flow sample. Transmural blood flow was considered the average of subepicardial, midmyocardial, and subendocardial blood flows.

At the end of each experiment, the LAD was cannulated at the occlusion site. Ten milliliters of saline and 10 mL of patent blue dye were injected at equal pressure into the LAD and left atrium, respectively, to delineate the anatomic area at risk (AAR) subjected to prolonged occlusion and reperfusion and the nonischemic normal zone, respectively. The heart was immediately fibrillated, removed, and sliced into serial transverse sections 6–7 mm in width. The unstained AAR was separated from the blue-stained normal area, and the two regions were incubated at 37°C for 30 min in 1% 2,3,5-triphenyltetrazolium chloride (TTC) in 0.1 M phosphate buffer adjusted to a pH of 7.4. TTC stains noninfarcted myocardium a brick red color because of the presence of a formazan precipitate, resulting from the reduction of TTC by dehydrogenase enzymes present in viable tissue. Infarcted myocardium remains unstained. After overnight storage in 10% formaldehyde, infarcted and noninfarcted myocardium within the AAR were carefully separated and weighed. IF was expressed as a percentage of the AAR.

Statistical analysis of data within and between groups under baseline conditions, during drug interventions, and following LAD occlusion and reperfusion was performed with multiple analysis of variance for repeated measures followed by application of Duncan’s modification of Student’s t-test. Changes within and between groups were considered statistically significant when the P value was less than 0.05. All data are expressed as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Thirty-eight dogs were instrumented to obtain 37 successful experiments. One glyburide-pretreated dog receiving levosimendan was excluded because of intractable ventricular fibrillation. During control experiments (n = 8, Table 1), LAD occlusion produced significant (P < 0.05) increases in left ventricular end-diastolic pressure and decreases in +dP/dtmax. After reperfusion of the LAD, +dP/dtmax remained reduced, and left ventricular end-diastolic pressure remained increased in dogs receiving vehicle. Levosimendan (n = 9) increased the heart rate and +dP/dtmax and decreased mean arterial pressure. In contrast to findings in dogs receiving vehicle, LAD occlusion did not alter left ventricular end-diastolic pressure and +dP/dtmax compared with baseline in levosimendan-treated dogs. However, after levosimendan was discontinued, +dP/dtmax decreased to a value similar to that observed in vehicle-control experiments after 3 h of reperfusion. Glyburide (n = 10) did not affect systemic hemodynamics. LAD occlusion and reperfusion caused hemodynamic effects in glyburide-pretreated dogs that were similar to those observed in dogs receiving saline. The hemodynamic effects of levosimendan were unaffected by glyburide (n = 10). Levosimendan produced significant increases in +dP/dtmax in glyburide-pretreated dogs, changes that were similar to those observed during levosimendan alone.


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  		Table 1. Hemodynamic Data
 
Levosimendan increased transmural myocardial blood flow (Figure 2) to the LAD and left circumflex coronary artery perfused regions. These levosimendan-induced increases in blood flow were attenuated by pretreatment with glyburide. Glyburide alone did not affect transmural blood flow in either region. Subendocardial coronary collateral blood flow (myocardial blood flow measured in the LAD-perfused region during LAD occlusion, Figure 3) was similar among groups; however, levosimendan increased subepicardial and midmyocardial collateral perfusion. Although glyburide alone had no effect on collateral blood flow, levosimendan-induced increases in collateral perfusion were significantly attenuated by glyburide. There were no differences between groups in transmural blood flow to the LAD region after 1 h of reperfusion (control: 1.74 ± 0.29; levosimendan: 1.18 ± 0.15; levosimendan + glyburide: 1.18 ± 0.16; glyburide alone: 1.93 ± 0.29 mL · min-1 · g-1).



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  		Figure 2. Levosimendan (LEVO) increased transmural myocardial blood flow to regions perfused by the left anterior descending (LAD) and left circumflex (LCCA; normal zone) coronary arteries compared with control (CON) experiments. Glyburide (GLB) pretreatment alone had no effect on myocardial perfusion, but attenuated LEVO-induced increases in blood flow. All data are mean ± SEM. * Significantly (P < 0.05) different from CON.

 


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  		Figure 3. Subendocardial myocardial perfusion to the left anterior descending-perfused region measured during left anterior descending occlusion (collateral perfusion) was similar among groups, but levosimendan (LEVO) increased subepicardial and midmyocardial collateral blood flow compared with control (CON) experiments. Glyburide (GLB) pretreatment alone had no effect on collateral perfusion but abolished LEVO-induced increases in coronary collateral blood flow. All data are mean ± SEM. * Significantly (P < 0.05) different from CON.

 
IF in dogs receiving vehicle (Figure 4) was 24 ± 2% of the AAR. Levosimendan reduced IF to <50% of the value observed in dogs receiving vehicle. Glyburide alone did not affect IF, however, the beneficial actions of levosimendan on IF were blocked by glyburide pretreatment. There were no significant differences in the area of the left ventricle at risk for infarction among groups.



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  		Figure 4. Myocardial infarct size expressed as a percentage of the left ventricle at risk for infarction was significantly reduced by levosimendan (LEVO) compared with control (CON) experiments. Glyburide (GLB) pretreatment alone had no effect on infarct size but abolished the protection afforded by LEVO. All data are mean ± SEM. * Significantly (P < 0.05) different from CON. {dagger} Significantly (P < 0.05) different from LEVO after GLB-pretreatment.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Pharmacological therapy for left ventricular dysfunction has been severely limited by adverse side effects, including drug-induced exacerbation of myocardial ischemia and increases in cardiovascular-related mortality (14). However, newer positive inotropic drugs having novel pharmacological characteristics may protect against these deleterious effects. For example, the phosphodiesterase inhibitor vesnarinone has recently been shown to limit IF by increasing adenosine release during reductions of coronary perfusion pressure and simultaneous increases in contractility (15). Adenosine receptors are coupled to KATP channels, and experimental evidence indicates that KATP channel activation is the end-effector of a cardioprotective signal transduction pathway activated during ischemic preconditioning (8,16,17). Pharmacological modulation of KATP channels may prove beneficial in patients at risk of myocardial ischemia, particularly those requiring inotropic support.

In the current study we investigated the hypothesis that the myofilament calcium sensitizing agent, levosimendan, may have novel cardioprotective actions. The results demonstrate that levosimendan markedly reduces IF via KATP channel-dependent mechanisms at a dose that simultaneously produces positive inotropic effects. The present results confirm and extend our previous findings indicating that levosimendan causes dose-related positive chronotropic, inotropic, and lusitropic effects in conscious dogs (12) and causes decreases in left ventricular afterload and preload in humans (7). In the present investigation, levosimendan increased heart rate and +dP/dtmax and decreased mean arterial pressure. In contrast to the findings in dogs receiving saline, +dP/dtmax and left ventricular end-diastolic pressure were maintained at baseline values during coronary artery occlusion. Remarkably, levosimendan reduced the extent of myocardial infarction despite increasing +dP/dtmax and did so at a dose previously shown to produce positive inotropic effects (12).

Levosimendan has been shown to decrease the extent of ischemic injury in isolated rabbit hearts subjected to a coronary artery occlusion; however, the mechanisms responsible for the protection observed were unclear (18). Using patch-clamp techniques, Yokoshiki et al. (5,6) recently demonstrated that levosimendan stimulates glyburide-sensitive KATP-channel currents in ventricular and arterial myocytes. Activation of KATP channels by levosimendan in myocytes was synergistic with those of nucleotide diphosphates (6). Such a mechanism may enhance the cardioprotective effects of levosimendan during myocardial ischemia by augmenting the action of increased intracellular adenosine diphosphate concentrations to stimulate KATP channels. In the present investigation, the cardioprotective, but not the systemic hemodynamic, effects of levosimendan were abolished by the KATP channel antagonist glyburide. These findings indicate that levosimendan activates KATP channels in vivo and also suggest that levosimendan-induced reductions of IF occur independently of the myofilament Ca2+-sensitizing properties of this drug.

The cardioprotective effects of levosimendan may also be attributed to the activation of KATP channels in coronary vascular smooth muscle. Levosimendan increases coronary blood flow (12), and while this drug may also inhibit cardiac phosphodiesterases (19), the contribution of phosphodiesterase inhibition to the coronary vasodilator effects of levosimendan is uncertain. In fact, recent evidence suggests that unlike milrinone, for example, phosphodiesterase inhibition may not be the major mechanism by which levosimendan causes coronary vasodilation. The administration of a specific cyclic adenosine monophosphate-dependent protein kinase antagonist did not attenuate the coronary vasodilator effects of levosimendan (20). Rather, levosimendan directly activates KATP currents and hyperpolarizes arterial smooth muscle cells in vitro, actions that were blocked by glyburide (5). Levosimendan also decreases intracellular calcium concentration by a mechanism consistent with opening of potassium channels and relaxes coronary arteries independently of intracellular calcium concentration (21).

Like levosimendan, KATP channel agonists decrease IF. In contrast to levosimendan, reductions in IF afforded by other KATP channel agonists were observed in the absence of increases in coronary collateral blood flow (9). Nonetheless, KATP channel agonists increase collateral blood flow (22,23) and dilate coronary collateral microvessels in a dose-dependent fashion (24), effects that are attenuated by glyburide. In the present investigation, levosimendan did not affect subendocardial collateral blood flow, but subepicardial and midmyocardial collateral blood flow were increased. Similarly, levosimendan-induced increases in coronary collateral blood flow were significantly attenuated by glyburide, and these findings support the contention that the coronary vasodilating actions of levosimendan are primarily caused by activation of KATP channels. Such KATP channel-mediated increases in collateral blood flow probably account, at least in part, for the protection afforded by levosimendan. However, the present experimental design does not differentiate between levosimendan-induced activation of myocardial versus coronary vascular smooth muscle KATP channels, and whether levosimendan causes reductions of IF when administered at a dose devoid of effects on coronary collateral blood flow is unknown. Recent evidence obtained in a rabbit model with a poorly developed coronary collateral circulation (18), however, suggests that activation of myocardial KATP channels may play an important role in IF reduction produced by levosimendan.

The findings of the current investigation must be interpreted within the constraints of several potential limitations. Myocardial oxygen consumption was not directly measured, and it is unknown if levosimendan-induced hemodynamic effects altered myocardial oxygen consumption of ischemic myocardium. The dose of glyburide used during these experiments was chosen based on previous work, using a similar time course during which glyburide blocked the cardioprotective effects of anesthetics via KATP channel activation and in which glyburide did not independently increase IF (11). Low doses of glyburide are selective for KATP channels and do not block the antiischemic effects of calcium channel blockers or sodium channel and calmodulin antagonists (25). Although pretreatment with low doses of glyburide attenuates KATP channel agonist-induced increases in collateral blood flow (23), the dose of glyburide used in the current investigation may have been insufficient to completely block activation of vascular smooth muscle KATP channels. For example, decreases in systemic vascular resistance during KATP channel activation with cromakalim requires significantly larger (20 mg/kg) doses of glyburide (26). Nonetheless, the dose of glyburide used was sufficient to block myocardial KATP channels and abolish the cardioprotection afforded by levosimendan.

In summary, the present results are in agreement with in vitro findings that levosimendan activates KATP channels (5,6) and demonstrate that levosimendan reduces IF via KATP channel-dependent mechanisms at a dose that produces concomitant positive inotropic effects. The relative contribution of levosimendan-induced activation of myocardial versus coronary vascular KATP channels remains to be investigated.


   Acknowledgments
 
This work was supported in part by an American Heart Association Grant-in-Aid 97-50634 (JRK), US Public Health Service grants HL 03690 (JRK) and HL 54280 (DCW), and Anesthesiology Research Training Grant GM 08377 (DCW). DCW is a recipient of funding from Orion-Pharma, Espoo, Finland.

The authors wish to thank Todd Schmeling, MS, and David Schwabe, BS, for technical assistance and Angela Barnes, BA, for preparation of the manuscript. The authors also thank Lasse Lehtonen, MD, PhD, of Orion-Pharma, Espoo, Finland, for his generous provision of levosimendan.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication August 30, 1999.




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O. Yildiz, C. Nacitarhan, and M. Seyrek
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M. Zaugg, E. Lucchinetti, C. Garcia, T. Pasch, D. R. Spahn, and M. C. Schaub
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B. F. McBride and C. M. White
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press