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Occurrence, specific binding sites and functional effects of endothelin in human cardiopulmonary tissue
A Hemsén1, A Franco-Cereceda, R Matran
1Department of Pharmacology, Karolinska Institute, Stockholm, Sweden.
Insights
Endothelin-1 (ET-1) is the most abundant and active peptide in the human heart and lung. This study found specific binding sites for ET-1, which causes potent vasoconstriction and bronchoconstriction.
Area of Science:
- Cardiovascular Physiology
- Pulmonary Medicine
- Endocrinology
Background:
- Endothelin (ET) peptides are potent vasoactive substances.
- The distribution and function of ET peptides in the human cardiopulmonary system require further elucidation.
Purpose of the Study:
- To investigate the presence and characteristics of endothelin-like immunoreactivity (ET-LI) and its binding sites in human cardiopulmonary tissues.
- To determine the biological activity of ET-1 compared to other ET peptides in the human heart and lung.
Main Methods:
- Immunoassay for ET-like immunoreactivity (ET-LI) detection.
- High-performance liquid chromatography (HPLC) for ET-LI characterization.
- Radioligand binding assays using radiolabeled ET-1.
- Scatchard analysis to characterize receptor binding.
- Functional assays measuring vasoconstriction and bronchoconstriction.
Main Results:
- Highest ET-LI levels were observed in the left anterior descending coronary artery, lung, right atrium, and pulmonary artery.
- Chromatographic analysis confirmed ET-LI in the lung and left ventricle as synthetic ET-1.
- Specific, high-affinity ET-1 binding sites with slow dissociation rates were identified in the lung, right atrium, and left ventricle.
- ET-1 demonstrated greater potency than ET-2 and ET-3 in displacing ET-1 binding and in causing vasoconstriction and bronchoconstriction.
Conclusions:
- ET-1 is the predominant and most biologically active endothelin peptide in the human cardiopulmonary system.
- Specific, high-affinity binding sites for ET-1 are present in the human heart and lung, suggesting a significant physiological role.
- ET-1's potent vasoconstrictive and bronchoconstrictive effects highlight its importance in regulating cardiopulmonary function.
Abstract:
Endothelin (ET)-like immunoreactivity (-LI) was detected in the human cardiopulmonary system, with the highest levels being found in the left anterior descending coronary artery, followed by the lung, right atrium, pulmonary artery, bronchus, pulmonary vein and left ventricle. Chromatographic characterization showed that the ET-LI in the lung and left ventricle corresponded to synthetic ET-1. Specific, high-affinity binding sites for ET-1, with an extremely slow dissociation rate, were found in the lung, right atrium and left ventricle. Displacement studies revealed a rank order of potency of ET-1 greater than ET-2 and sarafotoxin 6b greater than ET-3 and big ET-1. Scatchard analysis indicated a single receptor population in the lung (KD 1.53 x 10(-10) M) and left ventricle (KD 3.0 x 10(-11) M). In functional experiments, ET-1 evoked concentration-dependent, long-lasting vasoconstriction of a higher potency than that evoked by ET-2 and ET-3 in epicardial coronary arteries as well as in pulmonary arteries. ET-1 and ET-2 also showed bronchoconstrictor activity at considerably lower concentrations (threshold 10(-11) M) of ET-1 than those needed to cause vasoconstriction (10(-9) M). ET-LI, mainly consisting of ET-1, occurs in human cardiopulmonary tissue. Specific, high-affinity sites with irreversible binding for ET-1 are found in both the heart and lung. ET-1 is more potent than ET-2 or ET-3 in displacing ET-1 binding and in causing vasoconstriction and bronchoconstriction. Thus, in the human heart and lung, ET-1 seems to be the most abundant and biologically active of the endothelin peptides.