ROLE OF SARCOPLASMIC-RETICULUM IN LOSS OF LOAD-SENSITIVE RELAXATION IN PRESSURE-OVERLOAD CARDIAC-HYPERTROPHY

The loss of load-sensitive relaxation observed in the pressure-overloa ded heart may reflect a strategy of slowed cytosolic Ca2+ uptake to yi eld a prolongation of the active state of the muscle and a decrease in cellular energy expenditure. A decrease in the potential of the sarco plasmic reticulum (SR) to resequester cytosolic Ca2+ during diastole c ould contribute to this attenuated load sensitivity. To test this hypo thesis, both in vitro mechanical function of anterior papillary muscle s and the SR Ca2+ sequestration potential of female guinea pig left ve ntricle were compared in cardiac hypertrophy (Hyp) and sham-operated ( Sham) groups. Twenty-one days of pressure overload induced by coarctat ion of the suprarenal, subdiaphragmatic aorta resulted in a 36% increa se in left ventricular mass in the Hyp. Peak isometric tension, the ra te of isometric tension development, and the maximal rates of isometri c and isotonic relaxation were significantly reduced in Hyp. Load-sens itive relaxation quantified by the ratio of a rapid loading to unloadi ng force step in isotonically contracting papillary muscle was reduced 50% in Hyp muscles. Maximum activity of SR Ca2+-adenosinetriphosphata se (ATPase) measured under optimal conditions (37 degrees C; saturatin g Ca2+) was unaltered, but at low free Ca2+ concentrations (0.65 mu M) , it was decreased by 43% of the Sham response. Bivariate regression a nalysis revealed a significant (r = 0.84; P = 0.009) relationship betw een the decrease in SR Ca2+-ATPase activity and the loss of load-sensi tive relaxation after aortic coarctation. Stimulation of the SR Ca2+-A TPase by the catalytic subunit of adenosine 3',5'-cyclic monophosphate -dependent protein kinase resulted in a 2.6-fold increase for Sham but only a 1.6-fold increase for Hyp. Semiquantitative Western blot radio immunoassays revealed that the changes in SR Ca2+-ATPase activity were not due to decreases in the content of the Ca2+-ATPase protein or pho spholamban. Our data directly implicate a role for decreased SR functi on in attenuated load sensitivity. A purposeful downregulation of SR C a2+ uptake likely results from a qualitative rather than a quantitativ e change in the ATPase and possibly one of its key regulators, phospho lamban.