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)

Both integrins and endothelins (ETs) are known to play important roles in vascular remodeling via proliferation, apoptosis, and migration of vascular smooth muscle cells (VSMCs), whose dysfunctions have been implicated in the pathogenesis of end-organ damage associated with hypertension and arteriosclerosis. However, whether there is any interaction between endothelin-1 (ET-1) and integrins remains unknown. Therefore, the aim of the present study was to elucidate whether ET-1 regulates the expression of integrin alpha(v) in rat VSMCs. ET-1 dose- and time-dependently suppressed the integrin alpha(v) messenger RNA (mRNA) transcripts, as quantified by a real-time quantitative polymerase chain reaction (PCR) method, and decreased the transcriptional activity of integrin alpha(v) gene, as demonstrated by integrin alpha(v)-luciferase assay. The inhibitory effect of ET-1 on integrin alpha(v) gene expression was abrogated by an ETA receptor antagonist (BQ123) but not by an ET(B) receptor antagonist (BQ788). ET-1 also suppressed the cell surface expression of integrin alpha(v)beta5 and the adhesion to vitronectin, but not to fibronectin. These results demonstrate that the adhesion of vitronectin to rat VSMCs is inhibited by ET-1 via the ET(A) receptors by suppressing integrin alpha(v) gene transcription, suggesting that ET-1 is involved in regulation of vascular integrin alpha(v) gene expression.
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PMID:Suppression of integrin alpha(v) expression by endothelin-1 in vascular smooth muscle cells. 1113 Dec 77

Endothelins, endothelin-1 (ET1), endothelin-2 (ET2) and endothelin-3 (ET3), are the most potent vasoconstrictor peptides released by endothelial cells. ET production is stimulated by vasopressor hormones, platelet-derived factors, coagulation products and cytokines, whereas nitric oxide and prostacyclin reduce ET production. ET bind to ETA and ETB receptors and produce marked and sustained rise in blood pressure, intense vasoconstriction of coronary arteries and have positive inotropic and chronotropic effects on myocardium. Besides, they influence neuroendocrine, renal and smooth muscle functions. ET appears to function mostly as a paracrine or an autocrine hormone. ET may have a role in hypertension, atherosclerosis, heart failure, coronary artery disease, renal insufficiency, vascular hypertrophy, respiratory and cerebrovascular conditions. Several antagonists of ET acting at receptor level or influencing endothelin converting enzyme (ECE) are under investigation and have great potential as agents for use in the treatment of wide spectrum of disease entities and as biologic probes for understanding the actions of ET in human beings.
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PMID:Endothelins and anti-endothelins. 1122 90

Our previous studies have demonstrated that inhaled nitric oxide (NO) decreases nitric oxide synthase (NOS) activity in vivo and that this inhibition is associated with rebound pulmonary hypertension upon acute withdrawal of inhaled NO. We have also demonstrated that inhaled NO elevates plasma endothelin-1 (ET-1) levels and that pretreatment with PD156707, an ETA receptor antagonist, blocks the rebound hypertension. The objectives of this study were to further elucidate the role of ET-1 in the rebound pulmonary hypertension upon acute withdrawal of inhaled NO. Inhaled NO (40 ppm) delivered to thirteen 4-week-old lambs decreased NOS activity by 36.2% in control lambs (P<0.05), whereas NOS activity was preserved in PD156707-treated lambs. When primary cultures of pulmonary artery smooth muscle cells were exposed to ET-1, superoxide production increased by 33% (P<0.05). This increase was blocked by a preincubation with PD156707. Furthermore, cotreatment of cells with ET-1 and NO increased peroxynitrite levels by 26% (P<0.05), whereas preincubation of purified human endothelial nitric oxide synthase (eNOS) protein with peroxynitrite generated a nitrated enzyme with 50% activity relative to control (P<0.05). Western blot analysis of peripheral lung extracts obtained after 24 hours of inhaled NO revealed a 90% reduction in 3-nitrotyrosine residues (P<0.05) in PD156707-treated lambs. The nitration of eNOS was also reduced by 40% in PD156707-treated lambs (P<0.05). These data suggest that the reduction of NOS activity associated with inhaled NO therapy may involve ETA receptor-mediated superoxide production. ETA receptor antagonists may prevent rebound pulmonary hypertension by protecting endogenous eNOS activity during inhaled NO therapy.
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PMID:Role for endothelin-1-induced superoxide and peroxynitrite production in rebound pulmonary hypertension associated with inhaled nitric oxide therapy. 1150 44

Evidence suggests that endothelin receptor antagonists may have therapeutic potential for the chronic treatment of heart failure. In the current study, the effects of an orally active mixed endothelin-A/endothelin-B (ETA /ETB ) receptor antagonist (enrasentan) were assessed in a model of cardiac hypertrophy and dysfunction (spontaneously hypertensive stroke prone rats) maintained on a high-salt/high-fat diet. Echocardiography was used to quantify cardiac performance and left ventricular dimensions. Enrasentan (1,200 and 2,400 parts per million in the high-salt/high-fat diet) had no significant effects on body weight and systolic blood pressure. However, increases in heart rate were not observed in the enrasentan-treated groups at 12 weeks (p < 0.05). Enrasentan-treated groups exhibited significantly improved survival (90-95% vs. 30% [control rats] at 18 weeks; p < 0.001). Enrasentan treatments also increased stroke volume (at 8, 12, and 16 weeks) and cardiac index (at 8 and 16 weeks) 33-50% and 45-63%, respectively. Enrasentan treatments reduced the relative wall thickness (14-27% at 8 and 12 weeks), ratio of left ventricular mass to body weight (20% at 12 weeks), and ratio of terminal heart weight to body weight (16-23%, p < 0.05). Finally, circulating aldosterone concentration (54-57%) and proANF fragment (33%) were reduced in enrasentan-treated groups (54-57% and 33%, respectively). Mixed ETA /ETB receptor antagonism improves cardiac performance and attenuates ventricular remodeling and premature mortality in an aggressive hypertension model.
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PMID:Enrasentan improves survival, limits left ventricular remodeling, and preserves myocardial performance in hypertensive cardiac hypertrophy and dysfunction. 1158 31

Three endothelin family peptides (endothelin-1, -2 and -3) exert an extremely potent and long-lasting vasoconstrictor action as well as other various actions through stimulating two subtypes of receptor (ETA and ETB). Vascular endothelial cells produce only endothelin-1. Although the pharmacological actions of exogenous endothelin-1 have been extensively analyzed, the physiological roles of endogenous endothelin-1 have long been obscure. Using potent and selective receptor antagonists, endothelin-1 has been demonstrated to contribute slightly to the maintenance of regional vascular tone. In gene-targeted mice, endothelin family peptides and their receptors have been shown to play an important role in the embryonic development of neural crest-derived tissues. In addition to its potent vasoconstrictor action, endothelin-1 has direct mitogenic actions on cardiovascular tissues, as well as co-mitogenic actions with a wide variety of growth factors and vasoactive substances. Endothelin-1 also promotes the synthesis and secretion of various substances including extracellular constituents. These effects of endogenous endothelin-1 would appear to be naturally concerned with the development and/or aggravation of chronic cardiovascular diseases, e.g. hypertension, pulmonary hypertension, vascular remodeling (restenosis, atherosclerosis), renal failure, and heart failure. A great many non-peptide and orally active endothelin receptor antagonists have been developed, and shown to exert excellent therapeutic effects in animal models as well as human patients with these diseases.
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PMID:Basic and therapeutic relevance of endothelin-mediated regulation. 1172 53

The results of the Randomized Aldactone Evaluation Study (RALES) and of several experimental studies have indicated that excess aldosterone detrimentally affects cardiovascular morbidity and mortality by acting through both classical and non-classical mineralocorticoid receptors. The effects mediated through classical mineralocorticoid receptors entail enhanced sodium and water reabsorption, potassium loss and hypokalaemia, congestion, increased vascular resistance and hypertension. Those occurring through non-classical mineralocorticoid receptors located on myofibroblasts comprise cardiac hypertrophy and fibrosis, which may be due to a direct effect of aldosterone on collagen synthesis. Data obtained in primary aldosteronism patients demonstrated left ventricular hypertrophy, as well as changes in left ventricular filling that can be accounted for by cardiac fibrosis. Available clinical data indicate that in a considerable proportion of congestive heart failure (CHF) patients treated with angiotensin converting enzyme (ACE) inhibitors, aldosterone secretion can escape from blockade of the renin-angiotensin system, thus suggesting that additional mechanisms, besides angiotensin II, can play an important role in the regulation of aldosterone secretion. Compelling evidence indicates that endothelin (ET)-1 is overtly increased in severe CHF and thus is a likely candidate for the aldosterone 'escape' phenomenon in CHF. Endothelin-1 is expressed in the adrenal cortex, together with its receptor subtypes A (ETA) and B (ETB), and directly stimulates aldosterone secretion in different species, in humans by acting via both ETA and ETB receptor subtypes. Moreover, we have recently found that the novel endothelin peptide ET-1 (1-31), by acting as an ETA agonist, can also be involved in the regulation of growth of the adrenal cortex, as well as in the pathogenesis of Conn's adenoma. In this paper, we review the findings suggesting a relationship between activation of the ET-1 system, enhanced aldosterone secretion and cardiac fibrosis and discuss the implications of endothelin antagonism for cardiovascular disease.
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PMID:The endothelin-aldosterone axis and cardiovascular diseases. 1181 78

Recent studies indicated an enhanced expression of Endothelin (ET) in the kidney contralateral to the vascular clip in two-kidney, one-clip (2K-1C) Goldblatt hypertension. We proposed that the enhanced intrarenal ET production might be responsible for altered haemodynamic and excretory capability of the unclipped kidney (UK) of 2K-1C renovascular hypertensive rats. Therefore, we examined the changes in arterial pressure and split renal function in the clipped (CK) and UK simultaneously, in response to chronic administration of the selective ETA receptor blocker (A-127722), given orally at a dose of 30 mg/kg/day for 3 weeks starting from the beginning of the 4th week of clipping. Systolic pressure averaged 177 +/- 7 mmHg in control rats (n=15) and 164 +/- 9 mmHg in treated rats (n=16) and the difference was not statistically different. Glomerular filtration rate (GFR), renal plasma flow (RPF) and renal vascular resistance (RVR) in the UK were not different between control and treated groups. Data were then analyzed by classifying rats as moderate hypertensives (MAP < 180 mmHg), and severe hypertensives (MAP > 180 mmHg). In the moderately hypertensive group, average MAP was 143 +/- 5 mmHg and 138 +/- 4 mmHg in control (n=9) and treated (n=10) groups, respectively. In the severely hypertensive group, average MAP was 192 +/- 5 mmHg and 188 +/- 5 mmHg in control (n=6) and treated (n=6) groups, respectively. GFR and RPF were significantly improved in the UK of only the severely hypertensives who received the antagonist. However, the ET(A) antagonist blunted the sodium loss in both CK and UK of severely hypertensive rats. We conclude that ET(A) receptors do not play a role in the progression of hypertension in 2K-1C renovascular hypertensive rats. Yet, ET(A) receptors play an important role in altering renal hemodynamics of the unclipped kidneys in severe degrees of renovascular hypertension.
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PMID:Effects of endothelin-A receptor antagonism on bilateral renal function in renovascular hypertensive rats. 1186 May 25

Upon maintained on a 1% NaCl drinking solution beginning at 7 weeks of age, the stroke-prone spontaneously hypertensive rat (SHRsp) developed severe hypertension and stroke; most died by 16 weeks. The mechanism by which these diseases evolve remains unclear. Endothelin-1 (ET-1) is a potent, peptidic vasoconstrictor and is implicated in the pathogenesis of various cardiovascular, renal, and central nervous system diseases. The purpose of the present study was to compare the binding of [125I]ET-1 to the brain, heart, kidney, liver, and spleen membrane preparations of 16-week-old SHRsp and age-matched normotensive Wistar-Kyoto rats (WKY). The KD values for [125I]ET-1 binding to the corresponding tissues of the two strains were not significantly different, except in the brain (SHRsp: 17 +/- 1 pM; WKY: 24 +/- 1 pM). In contrast, the Bmax values measured in the brain, heart, kidney, and liver of SHRsp were 1.5- to 2.1-fold greater than those of their WKY counterparts. Competition of [125I]ET-1 binding to the membrane preparations by the specific ETA receptor antagonist BQ-123 or the specific ETB receptor agonist sarafotoxin S6c revealed a similar proportion of ETA and ETB receptor subtypes in the corresponding tissues of the two rat strains. These results indicate that ET-1 binding is upregulated in SHRsp and suggest that ET-1 may play a pathophysiological role in this animal model of genetic hypertension.
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PMID:Upregulation of endothelin-1 binding in tissues of salt-loaded stroke-prone spontaneously hypertensive rats. 1205 55

Essential hypertension is one of the most important risk factors for cardiovascular diseases. Its pathophysiological mechanism is unknown. Recent data suggests that deformability and aggregation of red blood cells may play an important role in the regulation of blood rheology in hypertension. Simultaneously there are reports suggesting that antihypertensive effects of angiotensin converting enzyme inhibitors (ACEI) could be counteracted by high doses of aspirin. We postulate that these effects could be related to the changes in blood rheology. Accordingly we designed a study to evaluate the effect of low or high dose of aspirin on deformability and aggregability of red blood cells from patients with essential hypertension. Deformability and aggregability of red blood cells were measured by laser diffractometer (Rheodyn SSD, Myrenne GmbH) and computerized automatic aggregometer (MA1 Myrenne GmbH, Germany), respectively. The effects of aspirin on deformability and aggregation of red blood cells were studied ex vivo in whole blood from three groups of patients with essential hypertension (group I: 10 patients receiving placebo, group II: 23 patients receiving 75 mg/day p.o. aspirin for 3 days, and group III: 23 patients receiving 300 mg/day p.o. aspirin for 3 days). Subjects in all groups received the same combination of antihypertensive agents consisting of: one of ACEI (enalapril or perindopril), one of beta-antagonists (metoprolol or bisoprolol), and diuretic agent (indapamid). In patients receiving high dose of aspirin (300 mg/day) we observed that erythrocyte aggregability was 25% higher than in the placebo group (MEA = 25.8 +/- 6 SD, vs MEA = 20.6 +/- 3 SD, p < 0.05). Aspirin had no effects on deformability of erythrocytes or on arterial blood pressure. High doses of aspirin or possibly also other nonsteroidal anti-inflammatory drugs (NSAID) in patients receiving antihypertensive therapy can directly affect rheological properties of the blood due to the activation of red blood cell aggregation. Increased aggregation of red blood cells during antihypertensive therapy may be an important indicator of the worsening of organ perfusion.
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PMID:[The effect of aspirin on rheological properties of erythrocytes in essential hypertension]. 1215 52

Hypertension is associated with enhanced peripheral vascular resistance, which may be mediated by enhanced vasoconstriction. The impact of the recently detected G-protein beta3-subunit gene C825T polymorphism on the response to the major pressor mediators has been studied in vivo in the human microcirculation. We assessed the effects of endothelin-1 (ET-1), angiotensin II (AT), endothelin-antagonists (BQ-123 and BQ-788) and noradrenaline (NA, each 10-16-10-8 mol) on vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers (13 with CC genotype, 12 TC/TT genotype) using laser Doppler flowmetry. The effects of endothelium-derived vasodilation on NA-induced effects were studied using the NO-synthase inhibitor l-nitro-monomethyl-arginine (L-NMMA) and the alpha2-adrenoceptor-antagonist yohimbine (YO). ET-1, AT and NA caused a dose-dependent vasoconstriction (P < 0.001). In carriers of the 825T allele the response to ET-1, AT and NA was significantly enhanced leading to a shift to the left of the dose-response curve of up to two log units (ET-1: P < 0.001 vs. CC; AT: P < 0.01 vs. CC; NA: P < 0.05 vs. CC). After pretreatment with L-NMMA or YO, NA induced vasoconstriction was no longer different between subjects with the CC- and CT/TT genotypes. However, following combined pretreatment with both L-NMMA and YO, vasoconstriction to NA was significantly potentiated in carriers of the T-allele. Vasodilatation to an ETA-antagonist (BQ-123) was more pronounced in the CT/TT genotype, while ETB-antagonism (BQ-788) led to a more pronounced vasoconstriction in the CT/TT genotype (not significant vs. CC). Healthy, normotensive carriers of the 825T-allele have enhanced vasoconstriction to ET-1, AT and NA in the skin microcirculation. This enhanced vasoconstriction appears to be partially antagonized by an enhanced release of endothelium derived vasodilators mediated by the stimulation of endothelial alpha2-adrenoceptors. The GNB3 C825T polymorphism is potentially an attractive pharmacogenetic marker to predict hormone-mediated responses in humans.
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PMID:Enhanced vasoconstriction to endothelin-1, angiotensin II and noradrenaline in carriers of the GNB3 825T allele in the skin microcirculation. 1217 18


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