Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Endothelin-B receptor (ET(B))-deficient rats have low-renin, salt-sensitive hypertension. We hypothesized this was caused by an absence of renal ET(B) signaling and performed a series of experiments to examine the effect of dietary sodium (Na) on endothelin-1 (ET1) expression and renal function in wild-type (WT) and ET(B)-deficient rats. We found that ET(B) deficiency, but not dietary Na, increases circulating and tissue (kidney and aorta) ET1 levels. Quantitative reverse-transcription polymerase chain reaction reveals that aortic and renal ET1 and endothelin-A receptor (ET(A)) mRNA, however, are similarly increased by dietary Na in ET(B)-WT and ET(B)-deficient rats. We then determined the effect of chronic ET(A) blockade on blood pressure (direct conscious measurements), urinary protein excretion, and creatinine clearance (Crcl). On a Na-deficient diet, ET(B)-deficient rats have mild proteinuria and impaired Crcl. On a high-Na diet, severe hypertension and renal dysfunction develop in ET(B)-deficient rats. Chronic ET(A) blockade prevents hypertension and renal injury. To determine the role of the renal versus the extrarenal endothelin system, we performed renal cross-transplantation. We found that ET(B) deficiency in the body is associated with renal injury and an impaired ability to excrete an Na load. We also found that ET(B) deficiency in the body affects blood pressure response to dietary Na. Expression of ET1 and ET(A) are regulated by dietary Na. ET(B) receptors outside of the kidney, likely by functioning as a clearance receptor for ET1, limit salt-sensitivity in rats.
Hypertension 2005 May
PMID:Extrarenal ETB plays a significant role in controlling cardiovascular responses to high dietary sodium in rats. 1580 64

Spontaneously hypertensive stroke-prone rats (SHR-SP) suffer spontaneous stroke in part as a result of abnormal cerebrovascular development. Reduction of regional cerebral blood flow in this model has already been demonstrated. This model has three distinct stages of hypertension: pre-hypertensive, typical hypertensive and malignant hypertensive. We investigated the level of endothelin-1 and its receptor expression in the frontal cortex of SHR-SP at the malignant hypertensive stage (35-40 weeks of age), during which time the rats suffer strokes. The cerebral endothelin-1 level, as determined by enzyme-linked immunosorbent assay, was highly increased at this severely hypertensive stage compared to their genetic control, normotensive Wistar-Kyoto rats. This upregulation was associated with an increased expression of endothelin-A receptor, however, another endothelin-1 receptor, endothelin-B, was downregulated. The regional cerebral blood flow in the frontal cortex was reduced by 60% in 40-week-old malignantly SHR-SP as compared to age-matched Wistar-Kyoto rats. Thus, cerebral endothelin-1 expression increased in malignant hypertension in SHR-SP. The enhanced endothelin-1 may activate the endothelin-A receptor, which would, in turn, result in reduced cerebral blood flow. Downregulation of the endothelin-B receptor may cause suppression of endothelium-derived relaxing factors in the brain of SHR-SP and be an underlying factor in their stroke susceptibility.
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PMID:Altered expression of endothelin and its receptors in the brain of SHR-SP at malignant hypertensive stage. 1583 56

We hypothesize that endothelin-A receptor stimulation contributes to the elevated blood pressure and superoxide production in endothelin-B receptor-deficient rats on a high salt diet. Experiments were conducted on homozygous endothelin-B-deficient (sl/sl) and wild-type rats (wt) fed a high salt diet (8% NaCl) for 3 weeks. Separate groups were given normal drinking water or water containing the endothelin-A receptor antagonist, ABT-627 (5 mg/kg per day; n = 8-9 in all groups). On a normal salt diet, (sl/sl) rats had a significantly elevated systolic blood pressure compared with wt (138 +/- 3 vs 117 +/- 4 mmHg, respectively; P < 0.05). High salt diet caused a significant increase in systolic blood pressure in (sl/sl) rats compared with wt (158 +/- 2 vs 138 +/- 3 mmHg, respectively; P < 0.05). Endothelin-A receptor blockade decreased systolic blood pressure in (sl/sl) rats on high salt (125 +/- 5 mmHg; P < 0.05 vs without antagonist) without affecting the systolic blood pressure in wt (119 +/- 4 mmHg). Aortic superoxide production (lucigenin chemiluminescence) and plasma 8-isoprostane were elevated in sl/sl rats and were significantly reduced by endothelin-A receptor blockade in sl/sl, but not in wt rats. These findings suggest that endothelin-1, through the endothelin-A receptor, contributes to salt-induced hypertension and vascular superoxide production in endothelin-B-deficient rats.
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PMID:ETA receptor blockade attenuates hypertension and decreases reactive oxygen species in ETB receptor-deficient rats. 1583 63

Sitaxsentan (SITAX; Thelin, Encysive Corporation, Bellaire, TX, U.S.A.) is a highly selective oral endothelin-A receptor antagonist. STRIDE-1, a 12-week randomized, doubleblind, placebo-controlled trial of sitaxsentan for pulmonary arterial hypertension showed significant benefit in 6-minute walk distance, functional class and hemodynamics. Pulmonary arterial hypertension clinical trials traditionally limit enrolment to class III/IV patients with idiopathic pulmonary arterial hypertension or pulmonary arterial hypertension related to connective tissue disease, who have a baseline 6-minute walk distance of < 450 m. In contrast, STRIDE-1 included milder cases: class II patients, no baseline 6- minute walk cut-off, and congenital heart disease patients. We now present the STRIDE-1 subset who would have qualified under traditional inclusion criteria. The results were: change for placebo (mean +/- SE) vs change for sitaxsentan (mean +/- SE) vs treatment effect (mean), all statistically significant: 6-minute walk (m): -26 +/- 13, 39 +/- 10, 65; mean right atrial pressure (mmHg): 2.1 +/- 0.8, -1.2 +/- 0.5, -3.3; mean pulmonary arterial pressure (mmHg): 0.4 +/- 1.5, -4.7 +/- 1.5, -5.1; cardiac index (L/min per m): -0.09 +/- 0.09, 0.38 +/- 0.06, 0.47; pulmonary vascular resistance (dyne.s.cm): 85 +/- 60, -274 +/- 47, -359. A 45% improvement in functional class was seen in sitaxsentan-treated patients (P = 0.0005). Thus, in the STRIDE-1 subpopulation that met enrolment criteria of previous pulmonary arterial hypertension trials, improvement in efficacy parameters with sitaxsentan therapy was even greater than seen in the entire STRIDE-1 population.
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PMID:STRIDE 1: effects of the selective ET(A) receptor antagonist, sitaxsentan sodium, in a patient population with pulmonary arterial hypertension that meets traditional inclusion criteria of previous pulmonary arterial hypertension trials. 1583 66

Endothelin receptor antagonists (ERAs) have been developed to block the effects of endothelin-1 (ET-1) in a variety of cardiovascular conditions. ET-1 is a powerful vasoconstrictor with mitogenic or co-mitogenic properties, which acts through the stimulation of 2 subtypes of receptors [endothelin receptor subtype A (ETA) and endothelin receptor subtype B (ETB) receptors]. Endogenous ET-1 is involved in a variety of conditions including systemic and pulmonary hypertension (PH), congestive heart failure (CHF), vascular remodeling (restenosis, atherosclerosis), renal failure, cancer, and cerebrovascular disease. The first dual ETA/ETB receptor blocker, bosentan, has already been approved by the Food and Drug Administration for the treatment of pulmonary arterial hypertension (PAH). Trials of endothelin receptor antagonists in heart failure have been completed with mixed results so far. Studies are ongoing on the effects of selective ETA antagonists or dual ETA/ETB antagonists in lung fibrosis, cancer, and subarachnoid hemorrhage. While non-peptidic ET-1 receptor antagonists suitable for oral intake with excellent bioavailability have become available, proven efficacy is limited to pulmonary hypertension, but it is possible that these agents might find a place in the treatment of several cardiovascular and non-cardiovascular diseases in the coming future.
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PMID:Endothelin receptor antagonists. 1621 61

Sitaxsentan is an orally active, selective endothelin-A receptor antagonist that may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictive effects of endothelin-A receptors, while maintaining the vasodilator and endothelin-1 clearance functions of the endothelin-B receptors. In its first randomized, placebo-controlled study, sitaxsentan improved exercise capacity assessed by the 6-min walk test, New York Heart Association functional class, cardiac index and pulmonary vascular resistance in New York Heart Association Class II, III and IV patients with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension related to connective tissue disease or congenital heart disease. Although doses of 100 and 300 mg once daily demonstrated equivalent efficacy, the lower dose had a better safety profile. Additional studies are ongoing to assess the relative safety and efficacy of 50 and 100 mg once-daily dosing. The most common side effects include rhinitis, headache, peripheral edema, chest pain, nausea, constipation, increased prothrombin time/international normalized ratio (in patients on warfarin), flushing and insomnia. As with other endothelin receptor antagonists, increases in hepatic transaminases have been observed with sitaxsentan. Initial studies using the selective oral endothelin-A receptor antagonist sitaxsentan in pulmonary arterial hypertension patients have revealed a favorable risk-benefit therapeutic profile with the 100 mg once-daily dose.
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PMID:Sitaxsentan: a novel endothelin-A receptor antagonist for pulmonary arterial hypertension. 1629 89

Leptin, the obese gene product, plays an important role in the regulation of cardiac function. However, the mechanism behind leptin-induced cardiomyocyte contractile response is poorly understood. This study was designed to examine whether endothelin-1 receptor and NADPH oxidase play any role in leptin-induced cardiac contractile response. Isolated murine cardiomyocytes were exposed to leptin (5, 50, and 100 nmol/L) for 60 minutes in the absence or presence of the ETA receptor antagonist BQ123 (1 micromol/L), the ETB receptor antagonist BQ788 (1 micromol/L), or the NADPH oxidase inhibitor apocynin (100 micromol/L) before mechanical function was studied. Superoxide levels were measured by dihydroethidium fluorescent dye and the superoxide dismutase-inhibitable reduction of cytochrome c. NADPH oxidase subunit expression (p22phox, p47phox, p67phox, and gp91phox) was evaluated with Western blot. Leptin depressed peak shortening and maximal velocity of shortening/relengthening (+/-dL/dt), prolonged the duration of relengthening (TR90) without affecting the time-to-peak cell shortening. Consistent with the mechanical characteristics, myocytes treated with leptin displayed a reduced electrically stimulated rise in intracellular Ca2+ (change in fura-2 fluorescence intensity) associated with a prolonged intracellular Ca2+ decay rate. All of the abnormalities were significantly attenuated by apocynin, BQ123, or BQ788. Intracellular superoxide generation was enhanced after leptin treatment, which was partially blocked by apocynin, BQ123, or BQ788. Leptin had no effect on p22phox and gp91phox but upregulated protein expression of p67phox and p47phox, both of which were inhibited by apocynin, BQ123, or BQ788. These results suggest that leptin suppresses cardiac contractile function in ventricular myocytes through the endothelin-1 receptor and NADPH oxidase-mediated pathway.
Hypertension 2006 Feb
PMID:Leptin regulates cardiomyocyte contractile function through endothelin-1 receptor-NADPH oxidase pathway. 1656 83

An impairment of cardiac norepinephrine (NE) reuptake via the neuronal NE transporter (NET) enhances the effects of increased cardiac NE release in heart failure patients. Increasing evidence suggests that aldosterone and endothelins promote sympathetic overstimulation of failing hearts. Salt-sensitive Dahl rats (DS) fed a high-salt diet developed arterial hypertension and diastolic heart failure as well as elevated plasma levels of endothelin-1 and NE. Cardiac NE reuptake and NET-binding sites, as assessed by clearance of bolus-injected [(3)H]NE in isolated perfused rat hearts and [(3)H]mazindol binding, were reduced. Treatment of DS with the mineralocorticoid receptor antagonist spironolactone preserved the plasma levels of endothelin-1 and NE, cardiac NE reuptake, and myocardial NET density. Moreover, the ventricular function and survival of spironolactone-treated DS were significantly improved compared with untreated DS. The alpha(1)-inhibitor prazosin decreased blood pressure in DS similar to spironolactone treatment, but did not normalize the plasma levels of endothelin-1 and NE, NE reuptake, or ventricular function. In a heart failure-independent model, Wistar rats that were infused with aldosterone and fed a high-salt diet developed impaired cardiac NE reuptake. Treatment of these rats with the endothelin A receptor antagonist darusentan attenuated the impairment of NE reuptake. In conclusion, spironolactone preserves NET-dependent cardiac NE reuptake in salt-dependent heart failure. Evidence is provided that aldosterone inhibits NET function through an interaction with the endothelin system. Selective antagonism of the mineralocorticoid and/or the endothelin A receptor might represent therapeutic principles to prevent cardiac sympathetic overactivity in salt-dependent heart failure.
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PMID:Spironolactone preserves cardiac norepinephrine reuptake in salt-sensitive Dahl rats. 1643 56

Systemic sclerosis (SSc, scleroderma) is a multisystem disease with a bad prognosis. No drugs have been shown to cure this disease. In view of its pathogenesis, in which immune responses are presumed to play an important role, immune suppressive therapies are widely applied in the treatment of SSc. Recent placebo-controlled trials with cyclophosphamide in patients with SSc complicated by alveolitis, show a modest but significant difference in pulmonary function tests in favour for the cyclophosphamide treated group. Treatment with prostacyclin analogues and endothelin-1 receptor antagonists appear to stabilize pulmonary arterial hypertension, a thus far fatal complication of SSc.
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PMID:[Treatment of systemic sclerosis]. 1681 40

Activation of the endothelin-1 system plays a key role in the pathogenesis of pulmonary arterial hypertension (PAH). The endothelin-1 receptor antagonist bosentan inhibits the action of endothelin-1 at both receptor subtypes (ET(A) and ET(B) receptors) and has been approved for PAH therapy since 2001. Recent data were presented at an international symposium in Barcelona in February 2006.
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PMID:[Pulmonary arterial hypertension. Therapy with the endothelin-1 receptor antagonist bosentan]. 1686 76


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