Endothelin: A New Cardiovascular Regulatory Peptide
Section snippets
BACKGROUND
The blood vessel wall has long been recognized as a participant in cardiovascular homeostasis through its regulation of thrombosis and also the inflammatory process. During the past decade, an endocrine role for the endothelial cells in the regulation of vascular smooth muscle tone has emerged. In 1976, Moncada and associates1 described the existence of prostacyclin within the blood vessel wall, and in 1980, Furchgott and Zawadzki2 reported the observation that acetylcholine-mediated
MOLECULAR STRUCTURE AND SYNTHESIS
The family of ET peptides consists of three distinct 21-amino acid chains, each containing four cystine residues connected by two disulfide bridges, a group of charged residues that form a sharp bend in the molecule, and a long hydrophobic carboxyl-terminal alpha helix (Fig. 1).5 These peptides, ET-1 (the original porcine and human ET), ET-2 (with two amino acid substitutions from ET-1), and ET-3 (with six amino acid substitutions), are coded for by three separate genes in the human, rat, and
CONTROL OF SECRETION
The presence of messenger RNA encoding for preproendothelin within endothelial cells provides further evidence of de novo endothelial generation of ET within large arteries.5 In vitro production of ET by endothelial cells has been demonstrated in several species, including pigs, rats,17 and humans.18
The mode of secretion of ET remains unclear. Ultrastructural analysis with use of electron microscopy demonstrates that endothelial cells do not possess substantial numbers of secretory granules.19
LOCALIZATION OF RECEPTORS
For further investigation of the role of ET, localization studies of ET binding sites have been performed in vitro and also in vivo by using autoradiographic labeling techniques with [125I]ET.16, 30, 31, 32, 33, 34, 35 In rat, guinea pig, monkey, and human tissue, ET binding sites have been identified not only in the cardiovascular system (in decreasing order of frequency in the cardiac nerves, atria, ventricles, and coronary arteries) but also in the lung (homogeneous distribution), kidney (in
ET AS A CIRCULATING HORMONE
ET may be produced in and released from endothelial cells to interact locally with vascular smooth muscle cells as an autacoid. Despite such a local activity, recent studies support a role for ET as a circulating hormone.36, 37 Studies from our laboratory, in which a sensitive radioimmunoassay was used with a lower level of detection of 0.5 pg/ml, established the presence of ET in plasma of normal humans at a mean circulating concentration of 2.36 pg/ml (Fig. 4). Because the antigenic
CARDIOVASCULAR ACTIONS
ET is the most potent vasoconstrictor known,5 and its administration results in contraction of vascular strips from humans and experimental animals in vitro.39, 40, 41, 42, 43, 44, 45 ET is more potent in its action on veins than on arteries; veins typically contract at a lower dose of ET than that required to contract arteries41, 46 (Fig. 5). Although similar maximal contraction is achieved, decreasing vessel diameter is associated with increasing potency of ET.47 The presence of the
PULMONARY ACTIONS
As previously described, ET-1 and ET-3 appear to be produced by endothelial cells of the pulmonary macrovasculature and microvasculature, as well as the bronchiolar respiratory epithelium.15, 76 Numerous binding sites for ET are present within the lung, and the distribution of these sites is homogeneous throughout the lungs.32 The role of the lung in the clearance of ET is controversial. During infusion of exogenous ET to pigs, Pernow and others77 reported a high degree of extraction of ET from
RENAL ACTIONS
ET has a profound effect on renal hemodynamics (Table 2). Autoradiographic studies in rats have localized ET receptors in the renal artery and vein, arcuate artery, interlobular artery, vascular bundle, glomerulus, and renal papilla.31, 34, 82 In the kidney, messenger RNA for ET has been detected in the cortical and medullary regions.83 Intravenous infusions and bolus injections of pathophysiologic concentrations of ET in rats and dogs result in a dose-dependent decrease in renal blood flow and
ENDOCRINE INTERACTIONS
Using the technique of tissue autoradiography, Koseki and associates30 and Davenport and colleagues34 demonstrated binding sites for ET in the adrenal gland. The finding of a high density of binding in the medulla and zona glomerulosa areas suggested the possibility of ET modulation of catecholamines and aldosterone biosynthesis.89, 90 Indeed, ET may stimulate aldosterone biosynthesis in dispersed zona glomerulosa cells of rabbit and calf.90, 91 In addition, we and others have reported the
CLINICAL IMPLICATIONS AND FUTURE PROSPECTS
The detection of plasma ET in numerous studies confirms its status as a circulating peptide, and the existence of receptors for ET in various nonvascular tissues suggests that ET may influence the regulatory function of a wide variety of tissues both within and outside of the cardiovascular system.
Evidence indicates that ET affects circulatory hemodynamics and the response to alterations in cardiorenal homeostasis in pathologic states in the human, and its association with various clinical
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Current address: Northwestern University, Chicago, Illinois.