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Cardiac responses and binding sites for endothelin in normal and cardiomyopathic hamsters
1Department of Pharmacology, Bio-Mega Inc., Laval, Quebec, Canada.
Insights
Endothelin-1 impacts heart function differently in dystrophic hamsters compared to normal ones, showing reduced positive inotropic effects in the atrium. Binding of endothelin-1 to tissue membranes remained similar across both hamster strains.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Animal Models of Disease
Background:
- Endothelin-1 (ET-1) is a potent vasoconstrictor peptide with diverse physiological roles.
- Dystrophic hamster strains, like CHF 147, exhibit cardiac pathologies mimicking human cardiomyopathies.
- Understanding ET-1's role in disease is crucial for developing targeted therapies.
Purpose of the Study:
- To compare the functional effects of endothelin-1 on cardiac tissues in dystrophic hamsters (CHF 147) versus age-matched controls (CHF 148).
- To investigate the binding characteristics of endothelin-1 in various tissues of both hamster strains.
Main Methods:
- Isolated spontaneously beating atria and field-stimulated right ventricular strips were used to assess inotropic and chronotropic responses to endothelin-1.
- Radioligand binding assays with [125I]endothelin-1 were performed on membrane preparations from atrium, ventricle, lung, kidney, and brain.
Main Results:
- Endothelin-1 induced dose-dependent positive inotropic and chronotropic effects in atria of both CHF 148 and CHF 147.
- A significantly less positive inotropic effect of endothelin-1 was observed in CHF 147 atria compared to CHF 148.
- Ventricular strips from CHF 148 showed greater force than CHF 147; endothelin-1 decreased tension in both, with no strain-specific difference.
- [125I]Endothelin-1 binding was high-affinity and irreversible in all tested tissues from both strains, with no significant differences between CHF 148 and CHF 147.
Conclusions:
- Dystrophic hamster atria exhibit a diminished positive inotropic response to endothelin-1, suggesting altered signaling pathways in cardiomyopathy.
- Despite functional differences in atrial contractility, endothelin-1 receptor binding appears preserved in dystrophic hearts and other tissues.
Abstract:
The effects of endothelin-1 in the spontaneously beating atrium and the field-stimulated right ventricular strip preparation and the binding of [125I]endothelin-1 to membrane preparations from the atrium, ventricle, lung parenchyma, kidney and brain were compared using the 90-day-old dystrophic hamster strain CHF 147 (a strain displaying marked cardiomyopathologies at this age) and its age/genetically matched normal control, CHF 148. In the atrium, endothelin-1 produced dose-dependent positive inotropic and positive chronotropic effects in both CHF 148 and CHF 147 over the dose range of 10(-8) M to 3 x 10(-7) M. However, although no significant difference between CHF 148 and CHF 147 was observed for the positive chronotropic effects of endothelin-1, it produced a small, but significantly less positive inotropic effect in CHF 147 compared to CHF 148 at endothelin-1 concentrations of 2 x 10(-8) M and 3 x 10(-8) M. Field-stimulated right ventricular strips from CHF 148 contracted with a greater force compared to those from CHF 147. Endothelin-1 produced a dose-dependent decrease in the developed tension of the field-stimulated ventricular strip preparation, the extent of which did not differ between CHF 148 and CHF 147. [125I]Endothelin-1 bound with high affinity and in an apparently irreversible manner to membranes from both CHF 148 and CHF 147 atrium, ventricle, lung parenchyma, kidney and brain. No significant differences were noted between CHF 148 and CHF 147 for [125I]endothelin-1 binding to membranes prepared from the various tissues.(ABSTRACT TRUNCATED AT 250 WORDS)