No abstract

In the Syrian cardiomyopathic hamster heart, abnormal cellular calcium regulation, resulting in cellular calcium overload, is believed to play a role in the pathogenesis of cardiac hypertrophy and failure. Alternatively, the primary abnormality may be coronary vasospasm, resulting in reperfusion-induced necrosis. According to the latter hypothesis, only those cells that suffer an ischemic insult would contain elevated calcium levels. To determine whether a generalized elevation in myocytic calcium exists in myopathic hamster hearts, we measured cellular and subcellular calcium concentrations by electron probe microanalysis in cryosections of 50-day and 96-day myopathic and control hearts, rapidly frozen in vivo. Total calcium content of ventricular homogenates from each group was also measured by atomic absorption spectrophotometry. No significant differences hi subcellular calcium were found by electron probe microanalysis among 50-day and 96-day myopathics and their age-matched controls. In 50-day myopathic and control hearts, mitochondria! calcium was 0.7±0.2 and 0.9±0.2, respectively, and A-band calcium was 3.0±0.4 and 2.6±0.4 nunol calcium/kg dry wt(±SEM). Results from 96-day animals were similar. Localized regions of elevated calcium were found only at sites of necrotic foci: in Na + -loaded cells (mitochondria: 4.7±1.3 (SEM) mmol/kg dry wt), in dying cells (mitochondria: 72±22 (SEM) mmol/kg dry wt) or as extracellular deposits (7-10 mol/kg dry wt). Total calcium content of hearts from myopathic hamsters, as determined by atomic absorption spectrophotometry, was also 13 times (50-day) and 50 times (96-day) higher than controls. These results demonstrate that there is a marked heterogeneity in cellular calcium content in myopathic hamster hearts, but the data do not support the hypothesis of a generalized cellular calcium overload. 9 In view of the early onset of many of these changes in Ca 2+ metabolism, it has been proposed that a general elevation of intracellular Ca 2+ may be an important initiating or aggravating factor in the etiology of the disease.10 " Alternatively, it has been proposed by Sonnenblick and coworkers 12 that the primary defect responsible for development of heart failure in myo hamsters may not be an abnormality in Ca 2+ handling by the myocytes themselves but an increased reactivity of the coronary arteries and arterioles. They and others have provided evidence for the existence, in myo hamsters, of coronary vasospasm in situ 13 31920 Ca 2+ content of isolated mitochondrial fractions has also been shown to be significantly elevated in myo hearts.1120 The approaches used in these studies are, however, limited in their ability to identify whether the observed elevation in cardiac and/or mitochondrial Ca 2+ is a homogeneous phenomenon throughout the heart. An alternative methodology, which avoids the problems associated with measurements of total tissue Ca 2+ by AA, is electron probe microanalysis (EPMA) of intracellular and subcellular concentrations of Ca 2+ and other elements in ...