Dynamic changes in sarcoplasmic reticulum function in cardiac hypertrophy and failure.
Previous studies have demonstrated that cardiac function changes with development of pressure overload-induced hypertrophy. The present study was undertaken to discover the basis for the changes in sarcoplasmic reticulum (SR) functions: uptake, (as related to the SR Ca2+ pump properties) and release in isolated, perfused hypertrophied rat hearts. Our results demonstrated significant prolongation of the time-to-90%-relaxation, both during the period of compensation (8 weeks after banding the ascending aorta, group HR1), when systolic function was preserved, and later with progressive hypertrophy (20 weeks after banding, group HR2) and contractile failure (20-22 weeks after banding, group F). The initial rates of the oxalate-supported SR Ca2+ uptake and the maximum transport rate (Vmax) of the SR Ca2+ pump, measured in the left ventricular homogenates, during blockade of the SR Ca2+ release channels with ruthenium red, were preserved in group HR1. To correlate early relaxation abnormalities with SR function, the [Ca2+] required for half-maximal pump activation (EC50) was examined and increased significantly in HRI vs. Sham1 (0.95+/-0.06 vs. 0.81+/-0.04 microM, P<0.05) indicating that the affinity of the SR Ca2+ pump for Ca2+ was reduced. The same tendency was demonstrated in groups HR2 (0.94+/-0.06 vs. 0.79+/-0.05) and F (0.89+/-0.05 vs. 0.78+/-0.05). In addition, with progression of hypertrophy we observed a significant decline in the amount of SR Ca2+ pump, as assessed by the Vmax, from 31.22+/-1.20 (Sham2) to 26.47+/-1.58 HR2) nmol/mg protein per min (P<0.05), and from 33.81+/-1.23 (Sham3) to 25.15+/-1.57 (F) nmol/mg protein per min, (P<0.01). This decrease was accompanied by a parallel reduction in the number of SR Ca2+ release channels by 14% (HR2) and 23% (F), as determined by maximum [3H] ryanodine binding (Bmax). These results suggest that pressure overload-induced changes in SR Ca2+ uptake (as reflected by Vmax and EC50) and SR Ca2+ release (as reflected by Bmax), both leading to diminished Ca2+ sequestration, may contribute to impaired cardiac relaxation with compensatory hypertrophy and failure.
Szymanska
G
G
Boston College, MA 02167, USA.
Strömer
H
H
Kim
D H
DH
Lorell
B H
BH
Morgan
J P
JP
D000465:Algorithms; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000502:physiology; D002303:Cardiac Output, Low / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D006332:Cardiomegaly / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D004396:Coloring Agents; D006439:Hemodynamics / Q000502:physiology; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000201:enzymology; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D012430:Ruthenium Red; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*
D004396:Coloring Agents; D019837:Ryanodine Receptor Calcium Release Channel; D012430:Ruthenium Red; D012433:Ryanodine; D000252:Calcium-Transporting ATPases; D002118:Calcium