An analysis of responses to levosimendan in the pulmonary vascular bed of the cat.
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 A(2) 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-N(5)-(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.


CONCLUSIONS
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.
De Witt
Bracken J
BJ
Department of Anesthesiology, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
Ibrahim
Ikhlass N
IN
Bayer
Erin
E
Fields
Aaron M
AM
Richards
Todd A
TA
Banister
Ronald E
RE
Kaye
Alan D
AD
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000097:blood*; D002415:Cats; D003326:Coronary Circulation / Q000187:drug effects; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006835:Hydrazones / Q000097:blood*; D054086:KATP Channels; D009569:Nitric Oxide / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects*; D011724:Pyridazines / Q000097:blood*; D000077464:Simendan
D018528:ATP-Binding Cassette Transporters; D002316:Cardiotonic Agents; D006835:Hydrazones; D054086:KATP Channels; D010726:Phosphodiesterase Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011724:Pyridazines; C092520:uK-ATP-1 potassium channel; D009569:Nitric Oxide; D000077464:Simendan; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3