In a rabbit model of aortic stenosis, cardiac glycoside uptake is increased in the failing myocardium and localizes to the actomyosin system as well as the T-system.
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Enhanced glycoside uptake in failing rabbit myocardium may affect dosing; leaves open human translation and toxicity implications.
In ten rabbits an operation to induce aortic valvular stenosis was performed. The rabbits were sacrificed two, three or four weeks after the operation and the myocardium was examined by means of electron microscopy. In the same rabbits H3-digoxin or H3-digitoxin was administered intravenously before the animals were sacrificed and the distribution of cardiac glycoside in the myocardium was examined by means of autoradiography. Similar studies were conducted in six normal rabbits. 2. Electron micrographs showed the myocardium of normal rabbits in a highly contracted state with a mean Z-Z interval of 1.2μ. In two weeks after the operation, electron micrographs of the myocardium showed decrease in glycogen granules, widening of Z-band, swelling of mitochondria, disappearance of cristae and matrix and swelling and widening of sarcoplasmic reticulum. In three weeks after the operation a very large number of mitochondria of various sizes were observed around myofibrils, thus occupying most of the intracellular space and presenting a picture of mitochondriosis. In four weeks or more after the operation, glycogen granules and mitochondria were decreased. Some cristae and matrix had disappeared and vacuoles and dense bodies were observed. A-band and H-band had disppeared in some myofibrils, thus presenting an amorphous picture. 3. The uptake of digoxin or digitoxin in the myocardium was the greatest in 1 1/2 to 2 hours or 4 to 8 hours, respectively, after the intravenous administration both in control and operated groups. The uptake was greater in the operated group sacrificed three weeks or more after the operation than in the control group. There was no significant difference in uptake between the left and right ventricles. 4. Grains of cardiac glycoside were observed in A-band, Z-band, T-system and mitochondria both in the control and operated groups. This indicated that cardiac glycoside acted not only on T-system but also on actomyosin system. In rabbits sacrificed three weeks or more after the operation, grains were also observed in M-line.
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Kazumi Maeda (1973) studied this question.
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