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 cancer chemotherapy, selective enhancement of drug delivery to tumor tissue is essentially important for increase of chemotherapeutic effects. An attenuated vasoconstrictive response to angiotensin II (Ang II) in tumors and a marked increase in tumor blood flow were observed compared with normal tissues during systemic hypertension induced by Ang II infusion. The phenomenon was absent when hypertension was provoked by endothelin-1 (ET-1). We assessed this response to characterize ET receptor and Ang II receptor density and affinity in normal and tumor tissues. The tumor cell line LY80 was transplanted to the skin in nude rats. Four weeks later the rats were sacrificed. [125I] ET-1 and [125I Sar1, Ile8]-Ang II were used to map the receptors for ET and Ang II in rat tissues using computerized in vitro autoradiography. A moderately high density of ET receptors, (ETB > ETA) was found in tumors. The Ang II receptors were markedly reduced in tumor tissues without changes in the affinity. These results suggest that the decrease in Ang II receptors but not ET receptors in tumors may explain the hemodynamic effect of Ang II-induced hypertension and ET-induced hypertension on tumor blood flow.
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PMID:Endothelin receptors and angiotensin II receptors in tumor tissue. 959 34

We previously reported that adenovirus-mediated overexpression of endothelin-1 (ET-1) elevates systemic blood pressure in rats. In this model, plasma big ET-1: ET-1 ratios were almost 30, whereas they were only 5 in the control group, suggesting that endothelin-converting enzyme (ECE) may be a rate-limiting step in the production of ET-1 under these conditions. To further investigate the role of ECE in vivo, we prepared recombinant adenovirus strains carrying a soluble, secretory form of bovine ECE-1 cDNA (Ad.CMV. secECE), human ET-1 cDNA (Ad.CMV.ET-1), and, as a control, E. coli lacZ (Ad.CMV.beta-gal). Ad.CMV.secECE (1-10 x 10(9) pfu/ml) was injected into the caudal vein of male Wistar rats and the animals were studied 96 h later. Immunoblot analysis of circulating plasma confirmed the expression of the soluble ECE-1. The plasma levels of big ET-1 and mature ET-1 were similar in Ad.CMV.secECE and Ad.CMV.beta-gal groups (0.3-0.5 pM). When Ad.CMV.secECE was co-injected with Ad.CMV.ET-1 (2.5 x 10(9) pfu/ml each), plasma ET-1 levels were significantly elevated compared to the control group co-injected with Ad.CMV.secECE and Ad.CMV.beta-gal (10.2 +/- 2.4 vs. 1.1 +/- 0.2 pM). Big ET-1 levels were threefold higher (3.7 +/- 1.1 vs. 1.2 +/- 0.4 pM), and systemic blood pressure was significantly elevated (132 +/- 3 vs. 90 +/- 3 mm Hg) in the Ad.CMV.secECE + Ad.CMV.ET-1 group. Administration of an ECE inhibitor (CGS 26303, 30 mg/kg) significantly reduced the blood pressure in the Ad.CMV.secECE + Ad.CMV.ET-1 group (from 125 +/- 5 to 74 +/- 6 mm Hg) but not in the control group (from 85 +/- 2 to 75 +/- 3 mm Hg). Infusion of an ETA antagonist (FR 139317; 0.2 mg/kg/min for 30 min) also significantly reduced the blood pressure only in the Ad.CMV.secECE + Ad.CMV.ET-1 group, without any significant effect in the control group. This study demonstrates that even though overexpression of ECE-1 in itself does not lead to systemic hypertension, the enzyme can be a crucial rate-limiting factor in the production of mature ET-1 in vivo. Furthermore, this model may prove to be useful for in vivo screening of ECE inhibitors.
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PMID:In vivo role of endothelin-converting enzyme-1 as examined by adenovirus-mediated overexpression in rats. 959 39

Endothelin-1, discovered in 1988, is a 21-amino-acid peptide and currently the most potent vasoconstrictor and pressor substance known. Generated by vascular endothelial cells in response to a variety of chemical and mechanical signals, endothelin-1 is known to potentiate the actions of other vasoconstrictor substances and act as a comitogen in addition to directly causing vasoconstriction. There is evidence that endothelin-1 may contribute to the pathophysiology of conditions associated with sustained vasoconstriction, such as hypertension and heart failure, vasospastic conditions, such as subarachnoid hemorrhage, and atherogenesis. Studies using endothelin receptor antagonists show that endothelin-1 plays an important role in the maintenance of vascular tone and blood pressure in healthy humans, predominantly via an effect on the vascular smooth muscle ETA receptors. The endothelin receptor antagonist bosentan also effectively lowers blood pressure in hypertensive subjects and produces sustained and favorable effects on systemic and pulmonary hemodynamics in patients with chronic heart failure. A good side-effect profile, together with a potential for inhibition of atherogenesis, makes the endothelin receptor antagonists a potentially interesting class of novel agents for the treatment of cardiovascular disease.
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PMID:Clinical experience with endothelin antagonists. 960 70

Endothelin-1 (ET-1) is thought to play an important role in the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Because hypertension is associated with an increased incidence of coronary artery disease, this study was designed to determine if coronary vascular contraction to ET-1 is altered in DOCA-salt hypertensive rats and to determine the effect of chronic treatment of DOCA-salt rats with the selective ETA receptor antagonist A-127722. Male Sprague-Dawley rats were divided into four groups: DOCA, Placebo, DOCA + A-127722, and Placebo + A-127722. A-127722 was administered in drinking water at a concentration of 8 mg/100 ml. After 3 wk, mean arterial pressure (MAP) was significantly enhanced in DOCA-salt compared with Placebo rats. A-127722 significantly inhibited the increase in MAP. Contraction to ET-1 (10(-11) to 3 x 10(-8) M) was measured in isolated coronary and mesenteric small arteries (200-300 micron, intraluminal diameter) maintained at a constant intraluminal pressure of 40 mmHg and was significantly impaired in vessels from DOCA-salt compared with Placebo rats. Dose-dependent contractions to KCl were also inhibited in coronary, but only minimally impaired in mesenteric, arteries of DOCA-salt rats. Inhibition of nitric oxide synthase activity did not restore contraction to ET-1 in coronary small arteries. However contractions to ET-1 were enhanced in mesenteric small arteries. Chronic treatment with A-127722 significantly restored contraction to ET-1 in coronary, but not in mesenteric, arteries of DOCA-salt rats. Because ETA receptor blockade impairs the development of hypertension and improves coronary vascular reactivity, these data indicate that ET-1 plays an important role in coronary vascular dysfunction associated with DOCA-salt hypertension.
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PMID:Coronary vascular reactivity is improved by endothelin A receptor blockade in DOCA-salt hypertensive rats. 960 15

Endothelin (ET)-1 has potent renal and systemic vasoconstrictor properties, and thus we investigated whether ET-1 plays a role in increasing blood pressure and decreasing renal function in DOCA-salt hypertension. After a right nephrectomy, rats had DOCA or placebo pellets implanted subcutaneously and were given saline or tap water to drink, respectively. Additional groups of rats were given the ETA receptor antagonist A-127722 in their water. Rats were maintained in metabolic cages for monitoring excretory function and food and water intake. Three weeks after surgery, mean arterial pressure (MAP) was recorded in the conscious rats via a carotid artery catheter. As expected, DOCA-salt rats had significantly higher MAP compared with uninephrectomized controls (197 +/- 6 vs. 133 +/- 3 mmHg). Creatinine clearance, used as an estimate of glomerular filtration rate, was significantly reduced in DOCA-salt rats (2.9 +/- 0.4 vs. 6. 8 +/- 0.3 dl . day-1 . 100 g-1 body wt in controls). ETA receptor blockade with A-127722 significantly reduced MAP (156 +/- 8 mmHg) but had no effect on creatinine clearance of DOCA-salt-treated rats (2.8 +/- 0.3 dl . day-1 . 100 g-1 body wt). Plasma ET-1 levels were significantly raised after DOCA-salt treatment (1.4 +/- 0.5 pg/ml vs. 0.4 +/- 0.1 pg/ml in controls). A-127722 treatment increased circulating ET-1 levels in both placebo (2.3 +/- 0.5 pg/ml) and DOCA-salt (5.6 +/- 0.7 pg/ml) rats. However, ET-1 mRNA expression in renal cortical and medullary tissue was not affected by either A-127722 or DOCA-salt treatments. Thus ETA receptors appear to play a role in the maintenance and development of DOCA-salt hypertension but not in the accompanying reduction of renal function.
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PMID:ETA receptor blockade attenuates the hypertension but not renal dysfunction in DOCA-salt rats. 968 85

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

Nitric oxide (NO) impairs endothelin (ET) formation and/or action in isolated vessels. We hypothesized that ET may magnify the consequences of NO formation blockade on receptor-operated dilation of resistance coronary vessels in conscious dogs. In conscious instrumented dogs, graded intracoronary (IC) doses of acetylcholine (ACh) were delivered before IC administration of Nomega-nitro-L-arginine methyl ester (L-NAME), after L-NAME, and after L-NAME plus IC bosentan, an ETA/ETB receptor blocker. Before L-NAME, ACh (100 ng. kg-1. min-1) increased coronary blood flow (CBF) by 43+/-4% from 47+/-6 mL. min-1. After L-NAME, ACh failed to increase CBF (-3+/-2% from 50+/-7 mL. min-1). CBF responses to ACh were partially restored (+10+/-2% from 50+/-7 mL. min-1, P<0.01) after the addition of bosentan. Bosentan alone (without L-NAME) did not alter CBF responses to ACh. Blockade of ETA (Ro 61-1790) but not ETB (Ro 46-8443) receptors partially restored CBF responses to ACh after L-NAME. Myocardial immunoreactive ET levels in the perfusion territories of the circumflex and left anterior descending coronary arteries did not differ. ETA-dependent tone magnified the inhibitory effects of blockade of NO formation on receptor-operated dilation to ACh in resistance coronary vessels. Presumably, stimulated NO release has an inhibitory action on endogenous ET production and/or action at the level of resistance coronary vessels.
Hypertension 1998 Nov
PMID:Endothelin-dependent tone limits acetylcholine-induced dilation of resistance coronary vessels after blockade of NO formation in conscious dogs. 982 42

Adrenomedullin, originally discovered in human pheochromocytoma, is a vasodilating and natriuretic peptide of vascular endothelial and smooth muscle cell origin. Although endothelin-1 (ET-1) has been implicated as a vasoconstricting and growth-promoting peptide of endothelial origin, it may more importantly function as an autocrine factor and release vasodilatory substances such as nitric oxide by mechanisms linked to the endothelin-B (ETB) receptor subtype. The present study was designed to establish that the ETB receptor stimulates the secretion of adrenomedullin from cultured canine aortic endothelial cells. We first sought to determine the presence and production of adrenomedullin in canine aortic endothelial cells using immunohistochemistry and Northern blot analysis, which revealed that adrenomedullin immunoreactivity and adrenomedullin mRNA were present in canine aortic endothelial cells. Second, adrenomedullin was time-dependently secreted from canine aortic endothelial cells, with a secretion rate of 15.7+/-1.5 pg/10(5) cells per 24 hours. Furthermore, immunohistochemistry revealed the presence of the ETB receptor in canine aortic endothelial cells, and ETB receptor stimulation by sarafotoxin S6c increased adrenomedullin production and secretion from canine aortic endothelial cells. Such actions were blocked with the ETB receptor antagonist IRL-2500 but not with ETA receptor antagonist FR-139317. These studies are the first to report an additional autocrine role of the ETB receptor in the release of vasodilating and natriuretic peptide adrenomedullin, and they suggest another important vasoactive system regulated by the ET receptor subtype.
Hypertension 1998 Nov
PMID:Autocrine role for the endothelin-B receptor in the secretion of adrenomedullin. 982 53

Endothelins (ET) are 21-aminoacid peptides produced ubiquitously, which were discovered originally as endothelial products. These peptides may play important roles in cardiovascular physiology and pathophysiology. As the pathophysiologic roles of endothelins in cardiovascular disease become increasingly apparent, the potential therapeutic use of endothelin antagonists or endothelin converting enzyme inhibitors is recognized. The main endothelin produced by the endothelium is ET-1. Endothelin-1 is overexpressed in the vascular wall of salt-dependent models of hypertension, such as DOCA-salt hypertensive rats, DOCA-salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, and in stroke-prone SHR, angiotensin II-infused rats and 1-kidney 1 clip Goldblatt hypertensive rats, but not in SHR, 2-K 1C hypertensive rats or L-NAME-treated rats. The vasoconstrictor effect of ET-1 may contribute to blood pressure elevation and its growth-promoting action to vascular hypertrophy in the hypertensive models which overexpress ET-1 in blood vessels. In rats without generalized activation of the endothelin system, expression of ET-1 is often enhanced in coronary arteries, which suggests a role for ET-1 in myocardial ischemia in hypertension. In rats overexpressing ET-1, ETA/B and ETA-selective antagonists lowered blood pressure slightly, and significantly reduced vascular growth, particularly of small arteries, suggesting that ET-1 has a direct effect on growth. Protection from renal injury and from stroke has also been demonstrated in hypertensive rats treated with endothelin antagonists. In normotensive human subjects endothelin-dependent tone can be shown in the forearm. In a study of mild hypertensive patients, the ETA/B antagonist bosentan reduced blood pressure similarly to an ACE inhibitor. Moderate to severe hypertensive patients presented enhanced expression of ET-1 mRNA in the endothelium of subcutaneous resistance arteries. In blacks with familial hypertension increased plasma levels of endothelin have been found. Thus, ET-1 may play a role in some experimental hypertensive models and in human hypertension. In summary, endothelial ET-1 may be overexpressed in the more severe forms of hypertension, and in certain special populations which may respond particularly well to endothelin antagonism. Endothelin antagonists may prove to be effective disease-modifying agents if in future clinical trials they are shown clinically to blunt vascular growth and endothelial dysfunction, reduce stroke and exert the cardioprotective and renal protective effects already reported in experimental hypertension. These agents could contribute to reduce the long-term complications of hypertension, which remains to be demonstrated in humans.
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PMID:Endothelin: role in hypertension. 983 May 7

We investigated the ability of the ETA receptor antagonist T-0115 and the angiotensin-converting enzyme (ACE) inhibitor imidapril hydrochloride to prevent hypertensive complications induced in rats by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), NG-nitro-L-arginine methyl ester (L-NAME) 500 mg/l, or L-NAME plus imidapril 10 mg/l in the drinking water. In rats treated with L-NAME 500 mg/l plus T-0115, T-0115 was given in the food at a dose of 0.2 mg/g food or 0.6 mg/g food. We then collected 24-h urine samples at 2, 4, and 6 wk, obtained blood samples at 6 wk, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90+/-0.65 vs. 0.05+/-0.02 mg/d/100 g in control), and the area of the left ventricular wall (83.3+/-3.0 vs. 69.8+/-1.8 mm2 in control). The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of T-0115 0.6 mg/g food with L-NAME ameliorated the tail-cuff pressure and the albuminuria (0.56+/-0.23 mg/d/100 g), although to a lesser extent than the changes seen with imidapril 10 mg/l. T-0115 0.6 mg/g food prevented left ventricular hypertrophy as effectively as imidapril 10 mg/l (70.8+/-1.8 with T-0115 vs. 68.3+/-2.7 mm2 with imidapril). Chronic inhibition of NO synthesis produced left ventricular hypertrophy and nephrosclerosis. Our results demonstrate that inhibition of the renin-angiotensin system morely effectively prevents nephrosclerosis than does the blockade of ETA receptors in a model of hypertension induced by chronic NO blockade. However, inhibition of the ET-1 pathway appeared to be as effective as ACE inhibitors in preventing left ventricular hypertrophy in this model.
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PMID:ET(A) receptor antagonist ameliorates nephrosclerosis and left ventricular hypertrophy induced in rat by prolonged inhibition of nitric oxide synthesis. 987 18


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