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Effects of endothelin-1 in the isolated heart under ischemic and cardioplegic conditions
1Medizinische Universitätsklinik, Würzburg, F.R.G.
Insights
Endothelin-1 effectively constricts coronary arteries in isolated rat hearts, even during ischemia. Its constrictor action requires extracellular calcium but is independent of heart mechanical activity.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
Background:
- Endothelin-1 (ET-1) is a potent vasoconstrictor peptide.
- Its effects on coronary circulation, especially under stress conditions like ischemia, require further elucidation.
Purpose of the Study:
- To investigate the vasoconstrictor effects of endothelin-1 on isolated rat hearts under normal, ischemic, and cardioplegic conditions.
- To determine the role of mechanical activity and extracellular calcium in endothelin-1's coronary constrictor response.
Main Methods:
- Isolated isovolumic rat hearts were perfused with Krebs-Henseleit buffer.
- Cumulative dose-response curves for endothelin-1 were generated under varying perfusion pressures (ischemia), with high KCl (cardioplegia), and in calcium-free buffer.
Main Results:
- Endothelin-1 dose-dependently reduced coronary flow in control hearts.
- The constrictor effect of endothelin-1 was preserved in hearts subjected to simulated ischemia (reduced perfusion pressure).
- Mechanical activity abolition (high KCl) did not alter the response, while extracellular calcium removal significantly diminished it.
Conclusions:
- Endothelin-1 is a potent coronary constrictor in isolated rat hearts, maintaining efficacy during ischemia.
- The vasoconstrictive action of endothelin-1 is independent of cardiac mechanical activity.
- Extracellular calcium is essential for the full constrictor response to endothelin-1, with intracellular stores likely contributing to residual effects.
Abstract:
We examined the effects of the vasoconstrictor peptide endothelin-1 in isolated hearts under ischemic and cardioplegic conditions. Isolated isovolumic rat hearts were perfused with Krebs-Henseleit buffer at constant pressure. Cumulative dose-response curves were obtained for endothelin-1 boluses of 0.04-400 pmol in four groups of hearts. Coronary flow decreased with increasing dosages and was almost abolished at 400 pmol in control hearts perfused at a constant pressure of 100 mm Hg. In hearts made ischemic by reducing coronary perfusion pressure to 35 mm Hg, thus reducing coronary flow by 76%, the constrictor effect of endothelin-1 was well preserved. The endothelin-1 dose-response curve was unaltered when hearts were perfused with buffer containing 30 mM KCl to abolish mechanical activity without reducing extracellular Ca2+ concentration. A fourth group of hearts was perfused with Ca2(+)-free buffer, thus eliminating the source of extracellular Ca2+ as well as mechanical activity. In this group, the constrictor response to endothelin-1 was largely, but not completely, abolished, with a maximal constrictor effect of only 19% as opposed to 87% in control hearts. We conclude that in isolated rat heart endothelin-1 is a potent coronary constrictor under ischemic perfusion conditions and that absence of mechanical activity does not affect the action of endothelin-1, for which the presence of extracellular Ca2+ is essential. The small residual constrictor response with Ca2(+)-free perfusion is probably due to release of Ca2+ from intracellular stores.