Related Experiment Video
Updated: Jul 13, 2026
Measurement of Endothelium-Dependent Vasorelaxation in the Mouse Thoracic Aorta Using Tensometric Small Volume Chamber Myography
Published on: August 12, 2022
Mechanisms of endothelin-1-induced decrease in contractility in adult mouse ventricular myocytes
K Nishimaru1, Y Miura, M Endoh
1Department of Cardiovascular Pharmacology, Yamagata University School of Medicine, Yamagata, Japan.
Insights
Endothelin-1 (ET-1) causes negative inotropy in mouse hearts by reducing calcium transients and myofilament sensitivity. This involves increased calcium extrusion via the Na+/Ca2+ exchanger, impacting cardiac contractility.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Cellular Mechanisms of Cardiac Function
Background:
- Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in cardiovascular disease.
- While ET-1 enhances contractility in most mammals, it paradoxically reduces it in mice.
Purpose of the Study:
- To investigate the cellular mechanisms behind ET-1's negative inotropic effect in adult mouse ventricular myocytes.
- To elucidate the role of calcium handling and myofilament sensitivity in ET-1-induced cardiac dysfunction.
Main Methods:
- Simultaneous recording of cell shortening and calcium transients in isolated mouse ventricular myocytes.
- Utilized the calcium-sensitive dye indo-1 for accurate measurements.
- Employed the Na+/Ca2+ exchange inhibitor SEA0400 to assess exchanger involvement.
Main Results:
- ET-1 decreased myocyte cell shortening and calcium transients in a dose-dependent manner.
- ET-1 reduced myofilament calcium sensitivity, indicated by a rightward shift in the calcium transient/cell-shortening relationship.
- The Na+/Ca2+ exchanger inhibitor SEA0400 attenuated ET-1's effects on calcium transients and cell shortening.
Conclusions:
- ET-1 induces negative inotropy in mouse ventricular myocytes via reduced calcium transients and myofilament calcium sensitivity.
- Increased calcium extrusion by the Na+/Ca2+ exchanger is a key mechanism underlying ET-1's effects.
- Retarded cell shortening may contribute to the observed decrease in myofilament calcium sensitivity.
Background And Purpose:
The potent vasoconstrictor polypeptide endothelin-1 (ET-1) plays an important pathophysiological role in progression of cardiovascular diseases and elicits prominent effects on myocardial contractility. Although ET-1 produces a positive inotropy in cardiac muscle of most mammalian species, it induces a sustained negative inotropy in mice. This study was performed to gain an insight into the cellular mechanisms underlying the negative inotropy in adult mouse ventricular myocytes.
Experimental Approach:
Cell shortening and Ca(2+) transients were simultaneously recorded from isolated mouse ventricular myocytes loaded with the Ca(2+)-sensitive fluorescent dye indo-1.
Key Results:
ET-1 decreased cell shortening in a concentration-dependent manner (pD(2) value of 10.1). The ET-1-induced decrease in cell shortening was associated with a decrease in Ca(2+) transients. In addition, the Ca(2+) transient/cell-shortening relationship was shifted to the right by ET-1, indicating decreased myofilament Ca(2+) sensitivity. The instantaneous relationship of the rising phase of the Ca(2+) transient and cell shortening was shifted to the right by ET-1. Decreased Ca(2+) transients and cell shortening induced by ET-1 were markedly attenuated by the specific Na(+)/Ca(2+) exchange inhibitor SEA0400.
Conclusions And Implications:
ET-1-induced negative inotropy in mouse ventricular myocytes was mediated by decreased Ca(2+) transients and myofilament Ca(2+) sensitivity. These data are entirely consistent with the involvement of increased Ca(2+) extrusion via the Na(+)/Ca(2+) exchanger in the ET-1-mediated decrease in Ca(2+) transients. Decreased Ca(2+) sensitivity may be due to retardation of cell shortening in response to a rise in Ca(2+) transients.
