Impaired Ca2+ Handling in Perfused Hypertrophic Hearts from Dahl Salt-Sensitive Rats
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<B>To clarify the correlation between intracellular Ca<SUP>2+</SUP> dynamics and level of Ca<SUP>2+</SUP>-regulatory proteins, changes in Ca<SUP>2+</SUP> handling and these proteins were investigated in a whole-heart experimental model of pressure-overload hypertrophy. We used 17-18-week-old male Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) fed a high-salt diet. We monitored the fura-2 fluorescence ratio, an index of cytoplasmic Ca<SUP>2+</SUP> concentration ([Ca<SUP>2+</SUP>]<SUB>i</SUB>), using a Ca<SUP>2+</SUP> analyzer in a retrograde perfused heart. Left ventricular pressure (LVP) and an electrocardiogram were simultaneously recorded. Ca<SUP>2+</SUP> handling was assessed by exposing the hearts to 2 min of low-Na<SUP>+</SUP> (70 mmol/l) perfusion to produce an increase in [Ca<SUP>2+</SUP>]<SUB>i</SUB> (<I>n</I> =6), which was sensitive to Ni<SUP>2+</SUP>, a blocker of the Na<SUP>+</SUP>/Ca<SUP>2+</SUP> exchanger (NCX). In another series, the hearts were stimulated at 2.5 to 5 Hz to determine the Ca<SUP>2+</SUP>-force-frequency relationship (<I>n</I> =6). DS rats showed marked cardiac hypertrophy without any signs of failure. The time-to-peak Ca<SUP>2+</SUP> transient was prolonged in DS compared with that in DR during normal beating. During low-Na<SUP>+</SUP> exposure, the time-to-peak diastolic [Ca<SUP>2+</SUP>]<SUB>i</SUB> (TTP) and the decay-time from peak [Ca<SUP>2+</SUP>]<SUB>i</SUB> (DT) were prolonged in DS compared with DR (TTP, 43.3±4.0 <I>vs</I>. 32.5±2.5 s, <I>p</I> <0.05; DT, 70.0±8.8 <I>vs</I>. 29.2±2.7 s, <I>p</I> <0.005). Following pretreatment with 10 mmol/l caffeine to inhibit sarcoplasmic reticulum (SR) function, TTP and DT were still prolonged in DS compared with DR (TTP, 64.2±9.7 <I>vs</I>. 37.0±5.8 s, <I>p</I> <0.05; DT, 55.8±12.6 <I>vs</I>. 26.0±5.7 s, <I>p</I> <0.05). The force (LVP)-frequency relationship was initially positive in DR but was negative at all times in DS (%LVP/2.5 Hz: DS, 90.3±2.0%; DR, 112.2±4.5%; <I>p</I> <0.05). Elevation of diastolic [Ca<SUP>2+</SUP>]<SUB>i</SUB> (percent increase of baseline) was greater in DS than in DR with increased stimulation (5 Hz: DS, 80.7±6.7%; DR, 52.1±5.9%; <I>p</I> <0.05). In Western blot analysis, the protein level of NCX was equivalent, whereas that of SR Ca<SUP>2+</SUP> ATPase (SERCA2) was significantly decreased in DS compared with DR. These results suggest that slowing of cellular Ca<SUP>2+</SUP> mobilization and removal is related to impaired Ca<SUP>2+</SUP> handling in late-phase cardiac hypertrophy. Both the activity of the NCX and that of the SR may be affected. The SR dysfunction may be associated with change in protein level of SERCA2. (<I>Hypertens Res</I> 2003; 26: 643-653)</B>
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