Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this report we demonstrate that ET-2, in addition to its powerful vasoconstrictor properties and its role in hypertension, is capable of creating a hypercoagulable (prothrombotic) state. This study was facilitated by the utilization of a sensitive modified recalcification time (MRT) test that can measure coagulation at all points in the coagulation spectrum. The MRT was determined on aliquots (1 ml) of citrated blood which were added to saline (MRTS), to 10 micrograms of endotoxin (MRTE), and to 10 pg of ET-2 (MRT ET-2). The mean values of MRTS, MRTE, and MRT ET-2 were 4.3 +/- 0.8, 3.7 +/- 1.0, and 3.9 +/- 0.8 min, respectively. There was a statistically significant difference between MRTE vs. MRTS and MRT ET-2 vs. MRTS using the two-tailed t-test (p < 0.02 and p < 0.005, respectively).
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PMID:Prothrombotic effects of endothelin-2 (ET-2). 827 42

Endothelins are produced by endothelial and epithelial cells, macrophages, fibroblasts, and many other types of cells. Their receptors are present in numerous cells, including smooth muscle cells, myocytes, and fibroblasts. Evidence now suggests that the three isoforms of endothelins (ET-1 and the other two related isopeptides, ET-2 and ET-3) regulate growth in several of these cells. Endothelin-1 influences DNA synthesis, the expression of protooncogenes, cell proliferation, and hypertrophy. The participation of ET in mitogenesis involves activation of multiple transduction pathways, such as the production of second messengers, the release of intracellular pools of calcium, and influx of extracellular calcium. Moreover, ET-1 acts in synergism with various factors, such as EGF, PDGF, bFGF, TGFs, insulin, etc., to potentiate cellular transformation or replication. Several of these factors may in turn stimulate the synthesis and/or the release of endothelins. The production and release of endothelins are also increased in acute and chronic pathological processes, e.g., atherosclerosis, postangioplastic restenosis, hypertension, and carcinogenesis. It is postulated that endothelins act in a paracrine/autocrine manner in growth regulation and play an important role mediating vascular remodeling in some cardiovascular diseases. The present review analyses the implication of endothelins (ET-1, -2, and -3) in physiopathology related to their growth regulatory properties.
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PMID:Growth regulatory properties of endothelins. 848 16

The endothelin family consists of three structurally similar isopeptides: ET-1, ET-2, and ET-3. The two receptor subtypes, ETA and ETB, have different receptor affinities for the isopeptides. Stimulation of ETA and ETB receptors results in vasoconstriction, and ETB stimulation also causes vasodilation. These receptors may have profound impact on the etiologies of various diseases, including heart failure and hypertension. Studies with endothelin-receptor antagonists in animals and humans with heart failure show promising short- and long-term results. The place of the agents in the treatment of essential hypertension remains controversial, but they may have a greater role in hypertensive blacks and transplant recipients.
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PMID:The role of endothelin in heart failure and hypertension. 969 45

Previous studies have characterized the endothelin peptides (ET-1, ET-2, ET-3) as strong vasoconstrictors which are possibly involved in the pathogenesis of cardiovascular disease. Whereas ET-1 and ET-3 have been characterized using a number of approaches, little is known about the function of ET-2. The aim of this study was to define the role of ET-2 in physiology and pathophysiology using a transgenic approach. Transgenic rats expressing a genomic construct of the human ET-2 gene were generated by microinjection of fertilized oocytes from Sprague-Dawley rats. Two transgenic lines were generated, and one line was further characterized in detail. Studies on mRNA expression demonstrated that the transgene is expressed predominantly in kidney, gastrointestinal tract, adrenal gland, lung, and brain. Plasma endothelin levels were elevated 2-fold, and big-endothelin levels were elevated 2.5-fold. Despite these alterations blood pressure in transgenic rats remained normal. Further analysis of transgenic animals revealed that endothelin receptors were not downregulated, and that infusion of exogenous human ET-2 results in an enhanced blood pressure response. These observations suggest the presence of counterregulatory mechanisms influencing the effects of endothelin on blood pressure. One of these mechanisms may involve the nitric oxide system since infusion of an inhibitor of nitric oxide synthase resulted in a greater blood pressure response than in non-transgenic littermates. Despite unchanged blood pressure, alterations were observed in organ development and function, namely of hearts and kidneys, indicating an interference between transgene expression and growth processes. Male rats seem to be more susceptible to endothelin actions. These data show that the elevation in endothelin-2 expression in this transgenic model does not induce hypertension but leads to changes at the end-organ level. Normotension is most likely due to compensatory mechanisms such as increased nitric oxide formation.
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PMID:Transgenic rats expressing the human ET-2 gene: a model for the study of endothelin actions in vivo. 1049 2

This study was performed to test the hypothesis that endothelin peptides differentially influence intracellular calcium concentration ([Ca(2+)](i)) in preglomerular microvascular smooth muscle cells (MVSMC), in part through activation of endothelin (ET)(A) receptors. Experiments were performed in vitro with the use of single MVSMC freshly isolated from rat preglomerular microvessels. The effect of ET-1, ET-2, and ET-3 on [Ca(2+)](i) was measured with the use of the calcium-sensitive dye, fura 2, and standard fluorescence microscopy techniques. Baseline [Ca(2+)](i) averaged 84+/-3 nmol/L (n=141 cells from 23 dispersions). ET-1 concentrations of 1, 10, and 100 nmol/L evoked peak increases in [Ca(2+)](i) of 48+/-16, 930+/-125, and 810+/-130 nmol/L, respectively. The time course of the [Ca(2+)](i) response was biphasic, beginning with a rapid initial increase followed by a sustained plateau phase or a period during which [Ca(2+)](i) oscillated sharply. Similar responses were observed after ET-2 administration. In contrast, ET-3 stimulated monophasic increases in [Ca(2+)](i) of only 14+/-5, 33+/-16, and 44+/-19 nmol/L at peptide concentrations of 1, 10, and 100 nmol/L, respectively. These responses are significantly smaller than responses to ET-1 or ET-2, respectively. The relative contributions of calcium mobilization and calcium influx in the response to ET-1 were also evaluated. Removal of calcium from the bathing medium did not significantly alter the peak response to 10 nmol/L ET-1 but abolished the late phase elevation of [Ca(2+)](i). These data demonstrate that endothelin peptides increase [Ca(2+)](i) in preglomerular MVSMC. The concentration-response profiles are consistent with the response involving activation of ET(A) receptors. Furthermore, these results suggest that ET-1 increases [Ca(2+)](i) by stimulating both the release of intracellular calcium and the influx of calcium from the extracellular medium.
Hypertension 2000 Jan
PMID:Endothelin-mediated calcium signaling in preglomerular smooth muscle cells. 1064 11

The precursor of endothelin-1, big endothelin-1, is considered to be a more reliable marker of systemic production of vasoactive peptide. However, it is largely unclear whether ET(B) receptor-dependent clearance and endothelium-derived relaxing factors affect the precursor in a similar manner to mature ET-1. These ET(B)-dependent modulations of big ET-1 and big ET-2 pressor properties were therefore studied in the anesthetized rabbit. When injected into the left cardiac ventricle, ET-1 and ET-2 (0.01 to 1 nmol/kg) each induced biphasic responses (a depressor followed by a pressor response), whereas big ET-1 and big ET-2 (0.1 to 3 nmol/kg) caused only protracted pressor responses. The highest dose of big ET-1 caused significantly greater responses than ET-1, ET-2, or big ET-2. A selective ET(A) receptor antagonist, BQ-123 (1 mg/kg), markedly reduced pressor responses to all 4 peptides, whereas blockade of ET(B) receptors with BQ-788 (0.25 mg/kg) sharply potentiated the responses to ET-1, ET-2, and big ET-1, but not to big ET-2. Indomethacin (10 mg/kg) sharply potentiated the pressor response to ET-1 (1 nmol/kg), but not big ET-1, at all time points. In control animals, ET-1, but not big ET-1, also triggered an indomethacin-sensitive increase in circulating prostacyclin. Finally, systemically administered big ET-1, but not big ET-2, induced a phosphoramidon-sensitive increase in plasma IR-ET. Our results suggest a significant limiting role of ET(B) receptors on pressor responses to big ET-1. In contrast, the same receptor entities do not modulate the hemodynamic properties of the ET-2 precursor, given that, unlike big ET-1, it is poorly converted in the pulmonary or systemic circulation in anesthetized rabbits.
Hypertension 2000 Mar
PMID:ET(B) receptor blockade potentiates the pressor response to big endothelin-1 but not big endothelin-2 in the anesthetized rabbit. 1072 May 86

The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)-protein-coupled receptors. ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1. ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.
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PMID:Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. 1106

Endothelins (ET-1, ET-2 and ET-3) are 21-amino-acid peptides with two disulfide bonds that belong to the sarafotoxin family. ET-1, ET-2 and ET-3 are produced endogenously from preproendothelin to give big endothelins, which are cleaved by endothelin-converting enzyme (ECE) to yield the active protein. Endothelin has been shown to play important physiological and pathological roles by interacting with its G-protein-coupled receptors. There are two cloned ET receptors: the ET(A) receptor, which is selective for ET-1, and the ET(B) receptor, which binds ET-1, ET-2 and ET-3 with similar affinities. Since the discovery of endothelin, and especially since the availability of peptide ET antagonists such as BQ-123 and BQ-788, and nonpeptide compounds such as bosentan, considerable effort has been spent on better understanding the role of endothelin and its receptor antagonists. As a result, endothelin has been implicated in a variety of serious diseases, such as congestive heart failure, hypertension, pulmonary hypertension and prostate cancer. Research in pharmaceutical and biotechnology laboratories has generated many endothelin antagonists with either sulfonamide or triaryl carboxylic acid scaffolds, and a number of ET(A)-selective or nonselective ET(A)/ET(B) endothelin antagonists have entered clinical trials. This article will review the small-molecule ET(A)-selective and nonselective ET(A)/ET(B) antagonists that are under clinical evaluation, and highlight a member of this group of compounds, sitaxsentan. A summary of the medicinal chemistry that led to the identification of sitaxsentan will be presented, followed by selected animal and human clinical trial data. (c) 2001 Prous Science. All rights reserved.
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PMID:Nonpeptide endothelin antagonists in clinical development. 1275 Jul 62

Endothelin (ET)-1 and ET-2 are potent vasoconstrictor peptides with mitogenic activity. In this study, we investigated roles of ET system in renin-angiotensin system (RAS)-mediated hypertension, using transgenic hypertensive mice (THM) with over-expression of both human renin and angiotensinogen genes. In the first step, it was revealed that expression of ET system was locally enhanced, i.e. increases in cardiac preproET-1 mRNA and renal preproET-2 mRNA in THM, compared with the control (wild type) mice. In the next step, we studied the chronic effects of an ET antagonist (SB209670) on THM. Blood pressure (BP) in THM was significantly higher than that in the normal mice during the investigation. However, in the later phase of the study, from 12 to 20 weeks of treatment, THM receiving SB 209670 showed significantly lower BP than that in THM receiving saline. SB 209670 treatment for 20 weeks significantly attenuated phenotypes of cardiac hypertrophy, vascular wall thickening and hypertensive nephropathy observed in THM, suggesting that the ETA/B receptor antagonist is also effective even in the extraordinarily activated RAS condition. These findings suggest that organ specifically activated ET system in THM develops the phenotypes, hypertension, cardiac hypertrophy, and hypertensive nephropathy.
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PMID:The endothelin receptor antagonist ameliorates the hypertensive phenotypes of transgenic hypertensive mice with renin-angiotensin genes and discloses roles of organ specific activation of endothelin system in transgenic mice. 1468 51

Endothelin-1 (ET-1), a peptide of 21 amino acid residues, is the most potent vasoconstrictor substance known and now it is understood to be one of a family of three mammalian vasoactive peptides that also includes ET-2 and ET-3. The endothelins (ETs) affect multiple organ systems and seem to be involved in the pathogenesis of many diseases such as hypertension, pulmonary hypertension, atherosclerosis, apoptosis inhibition and angiogenesis. The ETs exert their effects via activation of two distinct G-protein coupled receptor subtypes termed ET(A) and ET(B). To date a number of ET receptor ligands with good affinity and selectivity is known, nevertheless these compounds belong only to few chemical classes. The aim of this work was the identification of a "hit compound" with novel chemical structure, endowed with reasonable ET affinity and selectivity. Accordingly, a new class of (E)-alpha-[(1H-indol-3-yl)methylene]benzeneacetic acid derivatives (1-23) was synthesized for evaluation of their binding profiles.
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PMID:Novel (E)-alpha-[(1H-indol-3-yl)methylene]benzeneacetic acids as endothelin receptor ligands. 1604 72


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