Ouabain treatment is associated with upregulation of phosphatase inhibitor-1 and Na+/Ca(2+)-exchanger and beta-adrenergic sensitization in rat hearts.
Cardiac glycosides are widely used in the treatment of congestive heart failure. While the mechanism of the positive inotropic effect after acute application of cardiac glycosides is explained by blockade of the Na+/K+-pump, little is known about consequences of a prolonged therapy. Here male Wistar rats were treated for 4 days with continuous infusions of ouabain (6.5 mg/kg/day) or 0.9% NaCl (control) via osmotic minipumps. Electrically driven (1 Hz, 35 degrees C) papillary muscles from ouabain-treated rats exhibited shorter relaxation time (-15%) and a twofold increase in the sensitivity for the positive inotropic effect of isoprenaline. The density and affinity of beta1- and beta2-adrenoceptors as well as mRNA and protein levels of stimulatory (G(s)alpha) and inhibitory (G(i)alpha-2, G(i)alpha-3) G-proteins were unaffected by ouabain. Similarly, SR-Ca2+-ATPase 2A, phospholamban, ryanodine-receptor expression as well as the oxalate-stimulated 45Ca-uptake of membrane vesicles remained unchanged. However, mRNA abundance of the protein phosphatase inhibitor-1 (I-1) and the Na+/Ca2+-exchanger (NCX) were increased by 52% and 26%, respectively. I-1 plays an amplifier role in cardiac signaling. Downregulation of I-1 in human heart failure is associated with desensitization of the beta-adrenergic signaling pathway. The present data suggest that the ouabain-induced increase in I-1 expression might be at least partly responsible for the increased isoprenaline sensitivity and increased expression of NCX for the accelerated relaxation after chronic ouabain in this model.
El-Armouche
Ali
A
Institute of Experimental and Clinical Pharmacology, University Hospital Eppendorf, Hamburg, Germany.
Jaeckel
Elmar
E
Boheler
Kenneth R
KR
Boknik
Peter
P
Hertle
Boris
B
Neumann
Joachim
J
Eschenhagen
Thomas
T
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis; D002155:Calsequestrin / Q000096:biosynthesis; D002316:Cardiotonic Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004722:Endoribonucleases; D019204:GTP-Binding Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000099211:Phospholamban
D000318:Adrenergic beta-Agonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002155:Calsequestrin; D002316:Cardiotonic Agents; D002352:Carrier Proteins; D004722:Endoribonucleases; D019204:GTP-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol; D010042:Ouabain; D010749:Phosphoprotein Phosphatases; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban; C021042:protein phosphatase inhibitor-1; C097081:PPP1R8 protein, human