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CARDIOVASCULAR ANESTHESIA

An Analysis of Responses to Levosimendan in the Pulmonary Vascular Bed of the Cat

Departments of Anesthesiology and Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas

Address correspondence and reprint requests to Alan D. Kaye, MD, PhD, Department of Anesthesiology, Texas Tech University Health Sciences Center, 3601 4th St., Rm. 1C-282, Lubbock, TX 79430. Address e-mail to aneadk{at}ttuhsc.edu

	Abstract

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Calcium-sensitizing drugs, such as levosimendan, are a novel class of drug therapy for heart failure. We investigated the hypothesis that levosimendan is a pulmonary vasodepressor mediated through inhibition of phosphodiesterase, adenosine triphosphate (ATP)-dependent potassium channels, or both. We investigated responses to the calcium sensitizer levosimendan in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was increased to a high steady level with the thromboxane A₂ analog U-46619. Under increased-tone conditions, levosimendan caused dose-related decreases in lobar arterial pressure without altering systemic arterial and left atrial pressure. Responses to levosimendan were significantly attenuated, although not completely, after the administration of U-37883A, a vascular selective nonsulfonylurea ATP-sensitive K⁺-channel-blocking drug. Responses to levosimendan were not significantly different after the administration of the nitric oxide synthase inhibitor L-N⁵-(1-iminoethyl)-ornithine or the cyclooxygenase inhibitor sodium meclofenamate or when lung ventilation was interrupted. These data show that levosimendan has significant vasodilator activity in the pulmonary vascular bed of the cat. They also suggest that pulmonary vasodilator responses to levosimendan are partially dependent on activation of ATP-sensitive K⁺ channels and independent of the synthesis of nitric oxide, activation of cyclooxygenase enzyme, or changes in bronchomotor tone in the pulmonary vascular bed of the cat.

IMPLICATIONS: Calcium-sensitizing drugs, such as levosimendan, are a novel class of drug therapy for heart-failure treatment. The lung circulation affects both right- and left-sided heart failure. Levosimendan decreased lobar arterial pressure via a partial K⁺_ATP (potassium channel sensitive to intracellular adenosine triphosphate levels)-dependent mechanism. These data suggest that, in addition to calcium-sensitizing activity, levosimendan decreases pulmonary resistance, which may also aid in the treatment of heart failure.

	Introduction

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Cardiotonic drugs that sensitize the myocardium to calcium represent a novel class of therapy for the treatment of heart failure. Levosimendan, a pyridazinone-dinitrile discovered by using cardiac troponin C as a target protein, is a potent calcium sensitizer that improves the force development of muscle contraction without increasing the cytosolic calcium-ion concentration (1). Calcium sensitizers augment calcium binding to the calcium-specific regulatory site of cardiac troponin C. Levosimendan binds cardiac troponin C in a calcium-dependent manner and stabilizes calcium-induced conformational changes of troponin C, which promotes prolonged interaction of actin and myosin filaments during systole (2–4).

Currently, vasodilator drugs that reduce cardiac preload and afterload are also part of effective therapy in the treatment of heart failure. Clinically, phosphodiesterase III inhibitors (cyclic adenosine monophosphate [cAMP] specific, cyclic guanosine monophosphate inhibited), such as amrinone and milrinone, are used in the treatment of heart failure and as positive inotropic drugs in postoperative cardiac surgery patients (5,6). Levosimendan produces vasodilation both in vitro and in vivo and also decreases systemic vascular resistance in dogs and humans (7–9). However, the mechanism of the vasodilator action is not completely defined. It has been suggested that levosimendan vasodilation may be mediated through inhibition of phosphodiesterase III, potassium channels, or both (10–12). Potassium channels sensitive to intracellular adenosine triphosphate (ATP) levels (K⁺_ATP) play a role in mediating the response to reactive hyperemia in skeletal muscle, responses to hypoxia in the coronary and pulmonary vascular beds, and vasodilator responses to endothelium-dependent hyperpolarizing drugs, as well as vasodilator prostaglandins (13,14). Although levosimendan has been shown to dilate the systemic vasculature, little is known about its action in the pulmonary circulation. This study was, therefore, undertaken to investigate the hypothesis that levosimendan is a pulmonary vasodepressor mediated through inhibition of phosphodiesterase III or ATP-dependent potassium channels, or both. This hypothesis was investigated by using mechanistic pharmacologic inhibitors in the pulmonary vascular bed of the intact-chest cat under constant-flow conditions.

	Methods

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This study was performed with approval from the animal subjects committee at Tulane School of Medicine. Twenty-nine adult cats were sedated with ketamine hydrochloride and anesthetized with pentobarbital sodium. The animals were restrained in the supine position on a fluoroscopic table, and a uniform level of anesthesia was maintained. The trachea was intubated, and the animals spontaneously breathed room air. Systemic arterial (aortic) pressure was measured from the aorta, and IV injections were made into a catheter in the inferior vena cava.

For perfusion of the left lower lung lobe, a triple-lumen catheter was passed under fluoroscopic guidance from an external jugular vein into the artery to the left lower lung lobe. After heparinization, the lobar artery was vascularly isolated by distension of the balloon cuff on the perfusion catheter. The lobe was perfused with a perfusion pump by way of the catheter lumen beyond the cuff with blood withdrawn from a femoral artery. Lobar arterial pressure was measured from a second catheter port beyond the cuff on the perfusion catheter. The perfusion rate was adjusted so that lobar arterial perfusion pressure approximated mean pressure in the main pulmonary artery and was not changed thereafter. The flow rate ranged from 29 to 40 mL/min, and left atrial pressure was measured with a radiopaque catheter passed transseptally into the left atrium. Mean vascular pressures, measured with Spectromed (Oxford, CA) DTX Plus transducers zeroed at the right atrial level, were recorded on a Grass (Quincy, MA) Model 7 recorder after characteristic wave forms had been confirmed. This model has been described previously, and a schematic diagram of the experimental design is shown in Figure 1 (14).

View larger version (37K): [in this window] [in a new window]   Figure 1. Schematic diagram of experimental design. LAP = left atrial pressure; Lo AP = lobar arterial pressure; MAP = mean arterial blood pressure.

The second series of experiments investigated the hypothesis that levosimendan exerts a vasodepressor action in the pulmonary circulation via a K⁺_ATP-channel mechanism. The effects of U-37883A on responses to levosimendan, pinacidil, levcromakalim, cromakalim, nitric oxide solution, and adenosine were compared before and after administration of the vascular selective K⁺_ATP-channel antagonist in the pulmonary vascular bed of the cat. When pulmonary lobar vascular resistance was increased by infusion of U-46619, a thromboxane A₂ analog, the agonists were injected into the perfusion circuit distal to the pump in a random sequence.

The hypotheses that levosimendan exerted a vasodepressor effect via a nitric oxide or cyclooxygenase mechanism, or both, were investigated in the remaining experiments. The influence of L-N⁵-(1-iminoethyl)-ornithine (L-NIO; a nitric oxide synthase inhibitor) and sodium meclofenamate (a cyclooxygenase inhibitor) on responses to levosimendan was compared before and after the administration of L-NIO (10 mg/kg IV) or sodium meclofenamate (2.5 mg/kg IV) with U-46619-induced increases in lobar arterial pressure.

Levosimendan (Simdax^®; a gift from Orion Pharma Research, Espoo, Finland) was dissolved in dimethyl sulfoxide. Siguazodan and rolipram (SmithKline Beecham, Sussex, UK) were dissolved in 20% dimethyl sulfoxide and diluted with normal saline (15). Pinacidil (Eli Lilly, Indianapolis, IN) was dissolved in 300 µL of ethanol and 400 µL of 4 N HCl and diluted with normal saline. Levcromakalim and cromakalim (SmithKline Beecham) were dissolved in 20% ethanol-saline solution. Nitric oxide solution was prepared as described previously (16). The solvents for these drugs had no significant effect on baseline vascular pressure or on responses to the vasoactive drugs. Acetylcholine chloride, adenosine, sodium arachidonate (Sigma, St. Louis, MO), sodium meclofenamate (Warner Lambert-Parke-Davis, Ann Arbor, MI), L-NIO (Alexis Biochemical, San Diego, CA), and U-37883A (Upjohn, Kalamazoo, MI) were dissolved in normal saline. All solutions were prepared on a frequent basis and kept on crushed ice during an experiment. Solutions were stored in a freezer in amber bottles. All drugs were injected into the perfused lobar artery in fixed small volumes, and injections of the compounds were randomized. The thromboxane A₂ analog U-46619 (Sigma) was dissolved in 100% ethanol at a concentration of 10 mg/mL and was diluted in 0.9% saline. The thromboxane A₂ analog was then infused into the perfused lobar artery with a Harvard (Holliston, MA) infusion pump at rates (55–320 ng/min) required to increase lobar arterial pressures to values of 31–35 mm Hg.

Arterial blood gas tensions and pH were measured with a Corning (Palo Alto, CA) Model 178 analyzer and were in the normal range. All hemodynamic data are expressed in absolute units and are presented as mean ± SE. Responses represent peak changes, and data were analyzed by using a one-way analysis of variance and the Scheffé F test or a paired Student’s t-test (17). A P value of <0.05 was used as the criterion for statistical significance.

	Results

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Responses to levosimendan, siguazodan, rolipram, and pinacidil were compared in the pulmonary vascular bed of the cat, and these data are summarized in Figure 2. Under baseline conditions, when tone in the pulmonary vascular bed was at resting levels (12–16 mm Hg), injections of levosimendan into the perfused lobar artery in doses of 0.3 to 3 µg had no significant effect on lobar arterial pressure (data not shown). However, when tone in the pulmonary vascular bed was increased to a high steady value (34 ± 2 mm Hg; Table 1) with an infusion of the thromboxane A₂ analog U-46619, the administration of levosimendan in doses of 0.3–3 µg caused significant dose-related decreases in pulmonary arterial perfusion pressure (Fig. 2A). Left atrial, mean systemic arterial, systolic, and diastolic pressures were unchanged at the doses of levosimendan studied (Table 2). In terms of relative vasodilator activity in the pulmonary vascular bed, when doses of the compounds required to decrease lobar arterial pressure to 6.5 mm Hg (ED_6.5 mm Hg) were compared, levosimendan was significantly more potent than siguazodan, rolipram, and pinacidil. Siguazodan and rolipram were also significantly more potent than pinacidil at the ED_6.5 mm Hg (Fig. 2B).

View larger version (21K): [in this window] [in a new window]   Figure 2. A, Bar graph illustrating the decrease in lobar arterial pressure in response to injections of levosimendan in doses of 0.3 to 3 µg into the pulmonary vascular bed of the cat. B, Dose-response curves comparing decreases in lobar arterial pressure in response to levosimendan, siguazodan, rolipram, and pinacidil. The compounds were injected directly into the lobar artery, and baseline pressure was increased to a high steady value with an infusion of U-46619; n indicates the number of experiments.

View larger version (38K): [in this window] [in a new window]   Figure 3. Bar graph comparing responses to levosimendan, pinacidil, levcromakalim, cromakalim, nitric oxide solution, and adenosine before and after the administration of the K+ATP (potassium channel sensitive to intracellular adenosine triphosphate levels)-channel inhibitor U-37883A under increased-tone conditions. Compounds were injected directly into the lobar artery. n indicates the number of experiments. *Responses were significantly different from control.

View larger version (36K): [in this window] [in a new window]   Figure 4. A, Bar graph comparing responses to levosimendan and acetylcholine before and after the administration of the nitric oxide synthase inhibitor L-N5-(1-iminoethyl)-ornithine (L-NIO) (10 mg/kg IV). B, Bar graph illustrating the influence of sodium meclofenamate (2.5 mg/kg IV) on the decrease in pulmonary perfusion pressure in response to levosimendan under increased-tone conditions. n indicates the number of experiments. *Responses were significantly different from control.

	Discussion

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The results of this study demonstrate that levosimendan has vasodepressor activity in the pulmonary vascular bed under increased-tone conditions. The levosimendan decreases in lobar arterial pressure were dose dependent and significantly inhibited after the administration of U-37883A, indicating that they are partially mediated by K⁺_ATP channels. However, responses to levosimendan were not altered after the administration of L-NIO or sodium meclofenamate.

Clinical therapy for cardiac ventricular dysfunction has been limited by the adverse effects of pharmacologic drugs, including drug-induced exacerbation of myocardial ischemia and subsequent increases in cardiovascular-related mortality (18). An advantage to calcium sensitization is that it does not increase intracellular calcium, thereby reducing the chance of arrhythmias caused by spontaneous release of calcium from intracellular calcium stores. Also, because the quantity of calcium required for contraction is smaller during calcium sensitization, the energy required to handle calcium is decreased (19). Optimal cardiac decrease in both preload and afterload results in decreased energy consumption by the heart and is one of the most effective strategies for treatment of heart failure (20). In addition to sensitizing the myocardium to calcium, levosimendan decreases diastolic blood pressure in humans (9). Therefore, levosimendan may increase inotropy and decrease afterload and thus possess novel pharmacological characteristics, making it amenable to treatment of congestive heart failure.

Levosimendan induces dose-related decreases in lobar arterial pressure when tone in the pulmonary vascular bed is increased to a high steady level. Inasmuch as pulmonary blood flow was maintained constant, the decreases in lobar arterial pressure reflected decreases in pulmonary vascular resistance. In terms of relative vasodilator activity in the pulmonary vascular bed, the dose of levosimendan required to decrease lobar arterial pressure to 6.5 mm Hg (ED_6.5 mm Hg) was significantly smaller than the ED_6.5 mm Hg for siguazodan, a phosphodiesterase III (cAMP-specific, cyclic guanosine monophosphate-inhibited) inhibitor, and rolipram, a phosphodiesterase IV (cAMP- specific) inhibitor. Levosimendan, siguazodan, and rolipram were also significantly more potent than pinacidil, a K⁺_ATP-channel agonist, at the ED_6.5 mm Hg. Drugs that inhibit phosphodiesterase III, such as milrinone and amrinone, have been used in the treatment of congestive heart failure, whereas inhibitors of phosphodiesterase IV have been suggested to be useful in the treatment of asthma and chronic obstructive pulmonary disease (5,6,21). Phosphodiesterase III and IV inhibitors are potent vasodilators in the pulmonary vascular bed of the cat (15). These results demonstrate that levosimendan is significantly more potent than either of the Type III or IV phosphodiesterase inhibitors investigated, as well as the K⁺_ATP-channel agonist pinacidil. In terms of systemic pressure, levosimendan is also reported to decrease end-diastolic pressure in humans (1). However, levosimendan did not alter systemic end-systolic, systemic end-diastolic, or mean systemic arterial pressure in the cat. The reason for the difference in results is unknown but may be because the doses were relatively small in comparison to those that produce systemic cardiovascular effects in vivo in humans (1). The reason for the difference in results may also represent a difference in levosimendan metabolism, the species investigated, or reflexive mechanisms.

Levosimendan activates potassium channels sensitive to intracellular ATP levels (K⁺_ATP) in vascular arterial and cardiac ventricular muscle cells of the rat (12). Levosimendan also decreases cardiac infarct size via K⁺_ATP-channel-dependent mechanisms at a dose that simultaneously produces positive inotropic effects (22). This decrease in infarct size was inhibited by glyburide; however, the associated systemic hemodynamic mechanisms of levosimendan were not affected. This suggests a difference in the effects of levosimendan on cardiac versus systemic vascular smooth muscle. The results of this investigation in the feline pulmonary vascular bed show that U-37883A, a vascular selective, nonsulfonylurea guanidine K⁺_ATP-channel-blocking drug, attenuates decreases in lobar arterial pressure in response to levosimendan (14). U-37883A also attenuates responses to the K⁺_ATP-channel opener levcromakalim, the racemate cromakalim, and pinacidil. However, U-37883A did not alter responses to nitric oxide solution and adenosine. These data provide support for the hypothesis that the vasodilator response to levosimendan is mediated through smooth muscle hyperpolarization via the activation of K⁺_ATP channels in the pulmonary vascular bed. The observation that responses to levosimendan are reduced, but not completely blocked, by the K⁺_ATP-channel blocker may suggest that the K⁺_ATP-channel activity is not completely inhibited by the dose of the inhibitor used in this study. However, the dose used has been shown to nearly abolish the response to K⁺_ATP-channel openers. Therefore, additional mechanisms may be involved in mediating the response to levosimendan.

Pulmonary constrictor responses to the thromboxane A₂ analog U-46619 are inhibited by glybenclamide and enhanced by U-37883A (14,23). Whereas glybenclamide has been shown to be a thromboxane receptor antagonist, the explanation for the enhancement of thromboxane responses after the administration of U-37883A is uncertain. It is, however, unlikely that the thromboxane A₂ receptor-enhancing activity of U-37883A would interfere with the interpretation of these results, because the enhancement observed after U-37883A administration on responses to U-46619 was competitive in nature and tone in the pulmonary vascular bed and was increased to similar values before and after administration of the K⁺_ATP-channel-blocking drug.

Levosimendan inotropic action has been related to its ability to "sensitize" the myocardium to calcium (19). However, levosimendan vasodilation has been associated with a "calcium-desensitization" mechanism on coronary vascular smooth muscle (24). "Calcium-desensitization" (the opposite of "calcium-sensitization") decreases the force of muscle contraction without decreasing the smooth muscle cytosolic calcium-ion concentration (24). Previous studies in vitro have suggested that levosimendan vasodilation is not altered by a calcium-free medium or calcium entry blockade (25). Furthermore, levosimendan may have a direct effect on smooth muscle contractile or regulatory proteins (24). Levosimendan vasodilation may also occur through inhibition of cAMP-dependent phosphodiesterase (10,11). In isolated porcine coronary arteries, levosimendan potentiated the relaxant effect of isoprenaline (25). However, no direct data related to levosimendan’s mechanism of action are presented in support of either a direct effect on smooth muscle or a cAMP phosphodiesterase mechanism in the pulmonary vascular bed of the cat, because it is very difficult to establish these mechanisms by using an in vivo preparation. Potentiation of agonist-induced cAMP accumulation after inhibition of cAMP phosphodiesterase has been demonstrated in the isolated hindquarters circulation, but not in the pulmonary vascular bed, of the cat (26). Furthermore, inhibitors of protein kinase A have been demonstrated to be effective only in in vitro preparations (19). Therefore, although a significant portion of the levosimendan response is not inhibited by K⁺_ATP-channel antagonists, a direct effect on vascular smooth muscle or a cAMP-mediated mechanism is probable but remains to be investigated in the pulmonary vascular bed of the cat.

Previous studies demonstrated that levosimendan-induced increases in coronary blood flow are further enhanced after protein kinase G inhibition (19). To investigate whether nitric oxide mediates or modulates responses to levosimendan, L-NIO, a nitric oxide synthase inhibitor, was used. Pulmonary vasodepressor responses to levosimendan were not affected by the nitric oxide synthase inhibitor L-NIO, suggesting that levosimendan responses are independent of the release of nitric oxide. The observation that pulmonary vasodilator responses to acetylcholine were decreased indicates that nitric oxide release was inhibited by L-NIO treatment (27). These data are in agreement with previous results obtained in the pulmonary vascular bed of the intact-chest cat, where acetylcholine responses are inhibited after nitric oxide synthase inhibition (28). Although protein kinase G was not directly inhibited in this study, it is unlikely that levosimendan responses are mediated or modulated by protein kinase G, because L-NIO inhibits both basal and stimulated release of nitric oxide (27). The reason for the difference in responses to levosimendan in the coronary and pulmonary circulation is unknown but may represent a fundamental difference in responses between vascular beds.

The increase in coronary blood flow in response to levosimendan has also been reported to be independent of cyclooxygenase (25). In this study, pulmonary vasodilator responses to levosimendan were not altered by sodium meclofenamate, a cyclooxygenase inhibitor, in doses that blocked pressor responses to arachidonic acid. Therefore, studies in the coronary and pulmonary circulation agree that products in the cyclooxygenase pathway do not appear to mediate or modulate responses to levosimendan.

In conclusion, the results of this study show that levosimendan has significant vasodilator activity in the pulmonary vascular bed of the cat under increased-tone conditions. The decreases in lobar arterial pressure in response to levosimendan were dose dependent and were significantly inhibited after the administration of U-37883A, indicating that they are mediated in part by K⁺_ATP channels. However, responses to levosimendan were not altered after the administration of L-NIO or sodium meclofenamate or by main bronchus occlusion. These results indicate that responses to levosimendan are not dependent on the release of endothelium-derived nitric oxide or activation of cyclooxygenase. These data suggest that levosimendan may be useful in the treatment of disorders in which pulmonary pressure is increased.

	References

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