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Functional state of the endothelium determines the response to endothelin in the coronary circulation
1McGill University Centre for the Prevention of Cardiovascular Disease, Division of Cardiology, Royal Victoria Hospital, Montreal, Quebec, Canada.
Insights
The endothelium protects the heart from endothelin's constricting effects, potentially through mechanisms beyond just endothelium-derived relaxing factor (EDRF). This finding highlights the endothelium's crucial role in maintaining coronary blood flow.
Area of Science:
- Cardiovascular Physiology
- Endothelial Function
Background:
- Endothelin is a potent vasoconstrictor with known cardiovascular effects.
- The role of the endothelium and endothelium-derived relaxing factor (EDRF) in modulating endothelin's actions requires further investigation.
Purpose of the Study:
- To investigate the effects of endothelin on the heart.
- To explore the interaction between endothelin and endothelium-derived relaxing factor (EDRF) in the coronary circulation.
Main Methods:
- Isolated perfused rabbit hearts were used, with coronary flow maintained constant.
- Varying doses of endothelin were injected into the coronary circulation.
- The effects of indomethacin and haemoglobin on endothelin responses were assessed.
Main Results:
- Endothelin alone caused minimal changes in perfusion pressure but a slight increase in left ventricular pressure.
- Haemoglobin, which inhibits endothelium-dependent dilation, unmasked a dose-dependent endothelin-induced constriction.
- Air infusion augmented this constrictor response and reduced left ventricular function.
Conclusions:
- The endothelium significantly protects the coronary bed from endothelin's vasoconstrictor effects.
- This protection may involve mechanisms beyond EDRF release, possibly related to endothelial barrier or metabolic functions.
- These findings underscore the complex role of the endothelium in cardiovascular regulation.
Abstract:
STUDY OBJECTIVE - The aim was to study the effects of endothelin on the heart with special attention to an interaction with endothelium derived relaxing factor (EDRF). DESIGN - Bolus injections of various amounts of endothelin (1-300 ng) were given into the coronary circulation of isolated perfused rabbit hearts while coronary flow was held constant at 35 ml.min-1 and coronary perfusion pressure and other physiological variables were measured. The effects of indomethacin and haemoglobin on the responses were examined. EXPERIMENTAL MATERIAL - 15 New Zealand white rabbits, 1.0-1.5 kg, were used for the studies. The animals were anaesthetised and the hearts rapidly excised and perfused in the Langendorff manner. MEASUREMENTS and RESULTS - With coronary flow held constant, bolus injections of endothelin up to 300 ng caused no consistent increase in perfusion pressure, but resulted in a slight increase in left ventricular developed pressure. Indomethacin (10 microM) did not alter the response to endothelin; however, when endothelium dependent dilatation was inhibited by haemoglobin (10 microM), a dose dependent endothelin induced constriction was unmasked, with EC50 of 41 (SEM 15) ng, maximum +46(8) mm Hg. This constrictor response was further augmented by air infusion (0.5 ml), EC50 26(10) ng, maximum +102(12) mm Hg, and endothelin now caused a substantial dose dependent reduction in left ventricular contractile function. Endothelium dependent dilatation was not significantly reduced after air embolisation. CONCLUSIONS - The remarkable ability of the endothelium to protect against vasoconstrictor action of circulating endothelin in the coronary bed may not be due only to EDRF release, but perhaps also to an additional mechanism related to endothelial barrier of metabolic function.