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Altered subcellular Ca2+ regulation in papillary muscles from cardiomyopathic hamster hearts
E Keller1, C S Moravec, M Bond
1Department of Molecular Cardiology, Cleveland Clinic Foundation, Ohio 44195, USA.
Insights
Cardiac dysfunction in prefailure cardiomyopathic (CM) hearts stems from reduced sarcoplasmic reticulum (SR) calcium availability, not calcium overload. This impacts muscle contraction and response to calcium channel agonists.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Prefailure cardiomyopathic (CM) hearts exhibit cardiac dysfunction, with the underlying cause debated as either calcium (Ca2+) overload or reduced SR Ca2+ availability.
- Understanding subcellular Ca2+ handling is crucial for diagnosing and treating heart failure.
Purpose of the Study:
- To investigate whether cardiac dysfunction in prefailure CM hamster hearts is due to Ca2+ overload or decreased SR Ca2+ availability.
- To compare the effects of increased Ca2+ influx on cardiac function and subcellular Ca2+ distribution in CM versus normal hamster hearts.
Main Methods:
- Papillary muscles from 110-day-old CM and normal hamsters were used.
- The Ca2+ channel agonist BAY K 8644 was administered to assess Ca2+ influx effects.
- Subcellular Ca2+ levels (A-band, mitochondrial, junctional SR) were measured using electron probe microanalysis.
- Muscles were rapidly frozen during contraction or relaxation for analysis.
Main Results:
- CM muscles showed decreased tension development and reduced inotropic response to BAY K 8644 compared to normal muscles.
- No elevation in mitochondrial or A-band Ca2+ was observed in CM muscles, even with BAY K 8644 treatment.
- Junctional SR Ca2+ was significantly lower in CM muscles during relaxation, irrespective of BAY K 8644 treatment.
Conclusions:
- The findings do not support a Ca2+ overload hypothesis in prefailure CM hearts.
- Results indicate reduced Ca2+ availability in the sarcoplasmic reticulum (SR) for contraction activation in CM hearts.
- This reduced SR Ca2+ availability is a key factor in the cardiac dysfunction observed in prefailure CM hamsters.
Abstract:
To investigate whether cardiac dysfunction in prefailure cardiomyopathic (CM) hamster hearts is due to Ca2+ overload or alternatively to decreased availability of Ca2+ in the sarcoplasmic reticulum (SR), the Ca2+ channel agonist, BAY K 8644, was used to compare the effects of increased Ca2+ influx on function and subcellular Ca2+ distribution in papillary muscles from hearts of 110-day-old CM and normal hamsters. A band, mitochondrial, and junctional SR Ca2+ were measured by electron probe microanalysis in CM and normal papillary muscles, which were either untreated or pretreated with BAY K 8644. Muscles were then rapidly frozen during contraction or relaxation. The results showed decreased tension development and decreased inotropic response to BAY K 8644 in CM muscles versus normals. There was no elevation of mitochondrial or A-band Ca2+ in BAY K 8644-treated or untreated CM muscles frozen during contraction or relaxation compared with similarly treated normals. In muscles frozen during relaxation, junctional SR Ca2+ was lower in both untreated and BAY K 8644-treated CM muscles versus comparably treated normals. These results do not support the hypothesis of an increased sensitivity to Ca2+ in hypertrophied, prefailure CM hearts but do indicate that less Ca2+ is available in the SR for activation of contraction.