Journal
ACTA PHYSIOLOGICA
Volume 210, Issue 2, Pages 369-380Publisher
WILEY-BLACKWELL
DOI: 10.1111/apha.12194
Keywords
Ca2+ oscillations; development; E-C coupling; ET-1; heart; IP3
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Funding
- Finnish Heart Research Foundation
- Finnish Foundation for Cardiovascular Research
- Sigrid Juselius Foundation
- Academy of Finland
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AimSpontaneous activity of embryonic cardiomyocytes originates from sarcoplasmic reticulum (SR) Ca2+ release during early cardiogenesis. However, the regulation of heart rate during embryonic development is still not clear. The aim of this study was to determine how endothelin-1 (ET-1) affects the heart rate of embryonic mice, as well as the pathway through which it exerts its effects. MethodsThe effects of ET-1 and ET-1 receptor inhibition on cardiac contraction were studied using confocal Ca2+ imaging of isolated mouse embryonic ventricular cardiomyocytes and ultrasonographic examination of embryonic cardiac contractions in utero. In addition, the amount of ET-1 peptide and ET receptor a (ETa) and b (ETb) mRNA levels were measured during different stages of development of the cardiac muscle. ResultsHigh ET-1 concentration and expression of both ETa and ETb receptors was observed in early cardiac tissue. ET-1 was found to increase the frequency of spontaneous Ca2+ oscillations in E10.5 embryonic cardiomyocytes in vitro. Non-specific inhibition of ET receptors with tezosentan caused arrhythmia and bradycardia in isolated embryonic cardiomyocytes and in whole embryonic hearts both in vitro (E10.5) and in utero (E12.5). ET-1-mediated stimulation of early heart rate was found to occur via ETb receptors and subsequent inositol trisphosphate receptor activation and increased SR Ca2+ leak. ConclusionEndothelin-1 is required to maintain a sufficient heart rate, as well as to prevent arrhythmia during early development of the mouse heart. This is achieved through ETb receptor, which stimulates Ca2+ leak through IP3 receptors.
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