CELLULAR BASIS OF CONTRACTILE DERANGEMENTS OF HYPERTROPHIED FELINE VENTRICULAR MYOCYTES

The objective of this study was to further explore the cellular basis of the reduced rate and magnitude of contraction of feline left ventri cular myocytes with severe hypertrophy induced by slow progressive pre ssure overload. A 3.0 mm internal diameter band was placed around the ascending aorta of 12 young (8-10 weeks old) cats, and sham operations were performed in 13 others. This caused no major pressure overload i nitially, but 15 weeks later there was a significant pressure gradient across the band (56 +/- 14 mmHg) and the heart weight to body weight ratio had increased from 4.2-7 gm/kg. Contraction rates and magnitudes of myocytes isolated from the hearts with hypertrophy (LVH) were sign ificantly slower and smaller, respectively, than those from control (C ) animals. Indo-1 fluorescence transients in LVH myocytes were signifi cantly smaller in magnitude and longer in duration than in C, suggesti ng that: contractile defects result from Ca2+ derangements. Elevation of bath Ca2+ increased the peak Indo-1 fluorescence and the rate and m agnitude of contraction in all myocytes. At the bath Ca2+ which had ma ximal inotropic effects there were no differences in the peals. Indo-1 fluorescence in LVH and C myocytes, but contraction magnitude remaine d significantly smaller in LVH, This suggests that there are Ca2+-inde pendent contractile derangements in LVH, In support of this hypothesis , the relationship between contraction magnitude and the peak Indo-1 f luorescence (index of myofibrillar Ca2+ sensitivity) was significantly shifted in LVH myocytes, suggesting that myofibrillar Ca2+ sensitivit y was reduced. There was also a significant shift of the terminal port ions of hysteresis loops of cell length nu indo-1 fluorescence ratio, providing additional support for this idea. Experiments with isoproter enol suggest that it can reduce myofibrillar Ca2+ sensitivity in C, bu t not LVH myocytes. The idea that increased internal resistance to sho rtening (internal load) is responsible for the contractile defects of LVH myocytes was examined by defining the relationship between the rat e of relengthening and the magnitude of shortening. There was no signi ficant difference in this relation between C and LVH myocytes. In addi tion, colchicine (which depolymerizes microtubular tubulin) had no sig nificant effect on contraction magnitude in either C or LVH myocytes. These results suggest that the contractile properties of feline LVH my ocytes result from changes in cellular Ca2+ regulation and myofibrilla r Ca2+ sensitivity but not from changes in the internal loading. (C) 1 997 Academic Press Limited.