Muscarinic modulation of the sodium-calcium exchanger in heart failure.
BACKGROUND
The Na-Ca exchanger (NCX) is a critical calcium efflux pathway in excitable cells, but little is known regarding its autonomic regulation.


RESULTS
We investigated beta-adrenergic receptor and muscarinic receptor regulation of the cardiac NCX in control and heart failure (HF) conditions in atrially paced pigs. NCX current in myocytes from control swine hearts was significantly increased by isoproterenol, and this response was reversed by concurrent muscarinic receptor stimulation with the addition of carbachol, demonstrating "accentuated antagonism." Okadaic acid eliminated the inhibitory effect of carbachol on isoproterenol-stimulated NCX current, indicating that muscarinic receptor regulation operates via protein phosphatase-induced dephosphorylation. However, in myocytes from atrially paced tachycardia-induced HF pigs, the NCX current was significantly larger at baseline but less responsive to isoproterenol compared with controls, whereas carbachol failed to inhibit isoproterenol-stimulated NCX current, and 8-Br-cGMP did not restore muscarinic responsiveness. Protein phosphatase type 1 dialysis significantly reduced NCX current in failing but not control cells, consistent with NCX hyperphosphorylation in HF. Protein phosphatase type 1 levels associated with NCX were significantly depressed in HF pigs compared with control, and total phosphatase activity associated with NCX was significantly decreased.


CONCLUSIONS
We conclude that the NCX is autonomically modulated, but HF reduces the level and activity of associated phosphatases; defective dephosphorylation then "locks" the exchanger in a highly active state.
Wei
Shao-kui
SK
Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, USA.
Ruknudin
Abdul M
AM
Shou
Matie
M
McCurley
John M
JM
Hanlon
Stephen U
SU
Elgin
Eric
E
Schulze
Dan H
DH
Haigney
Mark C P
MC
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial; D002469:Cell Separation; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004336:Drug Antagonism; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009544:Niflumic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D013552:Swine; D013610:Tachycardia / Q000150:complications / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D018721:Muscarinic Agonists; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D019831:Sodium-Calcium Exchanger; C016276:8-bromocyclic GMP; D009544:Niflumic Acid; D002217:Carbachol; D010749:Phosphoprotein Phosphatases; D006152:Cyclic GMP; D007545:Isoproterenol