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The effect of hyperthyroidism on rat cardiac sarcoplasmic reticulum

University of British Columbia

Hyperthyroidism is an endocrine disease which can affect the cardiovascular system. Cardiac function is typically augmented by the disease resulting in increased contractile force and a decrease in the relaxation time of the ventricular muscle. Since the cardiac sarcoplasmic reticulum (SR) has been shown to be intimately involved in both contraction and relaxation of the heart, it was investigated whether it was altered in the hyperthyroid rat heart. Hyperthyroidism was induced by subcutaneous injections of triiodothyronine (T₃) (dissolved in 0.01 N NaOH) at a dose of 500 μg/Kg/day for three days. The approach taken to investigate possible T₃ mediated alterations in cardiac sarcoplasmic reticulum was to study the progression of the disease from the euthyroid state up to a point which has previously demonstrated augmented cardiac function. The effect of the treatment protocol was studied 12, 24, 48 and 72 hours after it was initiated. Ventricular weight was augmented at 48 and 72 hours (p< 0.05 and p< 0.01, respectively), and the SR yield was significantly increased 24 (p< 0.05), 48 (p< 0.05), and 72 (p< 0.01) hours after initiation of the treatment. The ratio of SR yield to ventricular weight was greater in the treated animals indicating that the SR yield was increased to a greater extent than the ventricular weight. The ATP-dependent oxalate-facilitated calcium transport activity of the SR preparation was determined at each of these times. There was no significant difference in the rate of calcium uptake at 12 hours. At 24 hours, the T₃ treated rat SR calcium uptake activity was significantly (p< 0.05) higher at all free calcium concentrations assayed (range 0.1-5.3 μM) . At 48 and 72 hours, the SR V[sub Ca] was also significantly increased (p< 0.01 in each case). The K[sub Ca] was not affected by the T₃ treatment at any of the time points studied. Phosphorylation of the SR at 24, 48 and 72 hours indicated that the increased calcium uptake activity was associated with a slight, but not significant, increase in the number of calcium pump sites at 24 hours, but significantly more calcium pump sites were labelled at 48 and 72 hours (p< 0.01 and p< 0.05, respectively). Therefore, the results of this study suggest that hyperthyroid rat cardiac SR may contribute to the cardiac manifestations of the disease. Since long chain acylcarnitines (LCAC) are known to affect membrane transport proteins, and lipid metabolism and tissue carnitine content are affected by hyperthyroidism, it was investigated whether the carnitine derivatives localized in the SR were affected by the T₃ treatment. The total carnitine content (including free, acid soluble and long chain carnitine) was significantly decreased 24 (p< 0.05), 48 (p< 0.05) and 72 (p <0.01) hours after initiation of the treatment. Acid soluble carnitine levels were not affected. LCAC levels were slightly (but not significantly) decreased at 24 hours, and significantly decreased at 48 and 72 hours (p< 0.05 and p< 0.01, respectively). There was a strong negative correlation (r= -.93) between the increased V[sub Ca] and the decreased LCAC content of the SR. These results suggest a possible relationship between T₃ mediated alterations in lipid metabolism and the increased calcium transport activity of the SR. However other factors may also be involved which contribute to both the augmented calcium transport and the decreased LCAC content of the hyperthyroid cardiac SR.

Text

2010-06-19

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http://hdl.handle.net/2429/25844

Pharmaceutical Sciences

University of British Columbia

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