Decrease in myocardial ryanodine receptors and altered excitation-contraction coupling early in the development of heart failure.
BACKGROUND
Rapid ventricular pacing for 1 day reduced myocardial contractile function without inducing heart failure in conscious, chronically instrumented dogs. After 4 to 7 weeks of pacing, myocardial contractility was depressed further and overt signs of congestive heart failure, eg, ascites, dyspnea, and edema, were evident.


RESULTS
The mechanical restitution response, a physiological index of calcium release, was depressed at 1 day of rapid ventricular pacing. Postextrasystolic potentiation was also depressed by a similar amount, 14 +/- 3%, at 1 day after pacing. The response to isoproterenol 0.2 microgram/kg per minute was depressed by a significantly greater amount (P < .05), 52 +/- 7%, at 1 day after pacing. 3H-ryanodine receptor binding fell from 1013 +/- 25 to 808 +/- 42 fmol/mg after 1 day of pacing and remained depressed at similar levels (782 +/- 61 fmol/mg) at 4 to 7 weeks when heart failure was manifest. Ryanodine receptor affinity was unchanged from control values. Neither dihydropyridine binding nor affinity for 3H-PN200-110 was changed from control levels. Within 5 days after recovery from 1 day of pacing, physiological responses to isoproterenol, postextrasystolic potentiation, and mechanical restitution recovered, as did 3H-ryanodine binding density.


CONCLUSIONS
These findings suggest that the changes in excitation-contraction coupling and potentially the sarcoplasmic reticulum calcium release channel occur early in the development of heart failure and therefore may be important in the pathogenesis of the contractile abnormalities in this disease state.
Vatner
D E
DE
Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Mass.
Sato
N
N
Kiuchi
K
K
Shannon
R P
RP
Vatner
S F
SF
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D005117:Cardiac Complexes, Premature / Q000503:physiopathology; D002303:Cardiac Output, Low / Q000503:physiopathology*; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006439:Hemodynamics; D007545:Isoproterenol / Q000494:pharmacology; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel; D016277:Ventricular Function, Left / Q000187:drug effects
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D007545:Isoproterenol