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)

The effects of metal chelators on endothelin (ET)-converting enzyme (ECE) activity in vivo were examined. Three compounds, (2,3-dimercapto-1-propanol (DMP), toluene-3,4-dithiol (TDT) and 8-mercaptoquinoline (8-MQ)), which inhibited ECE in in vitro studies, exhibited inhibitory activity towards big ET-1-induced sudden death in mice, while EDTA did not. Similar results were obtained in big ET-1-induced hypertension. Big ET-1-induced hemoconcentration was inhibited by pretreatment with 8-MQ or EDTA but not with DMP or TDT. The elevation of immunoreactive ET-1 (IR-ET-1) in plasma after administration of big ET-1 was inhibited by pretreatment with the three compounds but not by EDTA. On the other hand, no chelator inhibited the elevation of IR-ET-1 in lung tissue after injection of big ET-1. Taking into consideration the in vitro results, more selective chelating activity of the compounds towards Zn2+ rather than Ca2+ and Mg2+ may contribute to the inhibition of big ET-1-induced responses in vivo. The ET-1 formation involved in big ET-1-induced hemoconcentration may have different physiological characteristics from that involved in big ET-1-induced sudden death or hypertension.
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PMID:Inhibitory activities of metal chelators on endothelin-converting enzyme. II. In vivo studies. 820 18

Vascular endothelial cells are thought to play an important role in human aging as their senescence and detachment from a vascular wall may contribute to arteriosclerosis and high blood pressure in the elderly. We investigated the level of fibronectin (FN) expression in aortic endothelial cells aged in vivo, because FN is necessary for cell attachment and spreading and its increased expression had been shown in aging fibroblasts. The results showed that the steady state level of expression of FN mRNA increased with advancing donor age, while the labeling index of cultured cells decreased with age. Furthermore, the increased level of FN expression clearly correlated with an increase in cell area. In order to explore whether these changes reflected exhaustion of proliferation potential in vivo, we examined FN expression in human umbilical vein endothelial (HUVE) cells aging in vitro. Very similar results were obtained, supporting the idea that vascular endothelial cells age in vivo by using up division potential. Furthermore, we investigated the level of endothelin (ET) -1 mRNA expression during in vitro cellular aging of HUVE cells. The results showed that the expression of ET-1 gene was also up-regulated when the culture became old. It is very interesting that the genes for quite different proteins of FN and ET-1 are both up-regulated during cellular aging.
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PMID:Modulation of gene expression during aging of human vascular endothelial cells. 825 3

To determine whether endothelin (ET) has a role in maintaining circulatory support during hypotensive hemorrhage, we (1) examined cardiac and systemic hemodynamics after a 6-mL hemorrhage in the presence and absence of the ETA receptor blocker BQ-123, (2) examined cardiac and systemic hemodynamics during BQ-123 infusion in nonhemorrhaged rats, (3) measured changes in circulating immunoreactive endothelin (IR-ET) after a 6-mL hemorrhage, and (4) infused pathophysiological doses of ET-1 into rats anesthetized with thiobutabarbital. Twenty minutes after hemorrhage, cardiac output and mean arterial pressure had stabilized in part because of an increase in systemic vascular resistance from 0.86 +/- 0.04 (baseline) to 1.04 +/- 0.05 (20 minutes) mm Hg/mL per minute. The rise in systemic vascular resistance was temporally associated with a significant (24%) increase in circulating IR-ET from 29 +/- 2 to 36 +/- 3 pg/mL 20 minutes after hemorrhage. During BQ-123 infusion mean arterial pressure at 5, 10, and 20 minutes after hemorrhage was 9 +/- 2, 23 +/- 4, and 23 +/- 3 mm Hg lower than values obtained after hemorrhage alone (P < .05). Mean arterial pressure was unaffected by BQ-123 infusion at baseline and 30 minutes after hemorrhage. Systemic vascular resistance was not affected at baseline by BQ-123 infusion. However, systemic vascular resistance was significantly lower 5, 10, 20, and 30 minutes after hemorrhage during BQ-123 infusion compared with hemorrhage alone at each time point. Infusion of BQ-123 into nonhemorrhaged rats had no effect on mean arterial pressure, systemic vascular resistance, or cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Feb
PMID:Endothelin blockade lowers total peripheral resistance in hemorrhagic shock recovery. 830 30

The objectives of this study were to determine plasma levels of endothelin (ET) in a genetic model of hypertension and in control rats during control conditions and in response to short-term volume expansion with saline. Okamoto spontaneously hypertensive rats (SHR) and control Wistar-Kyoto (WKY) rats were used in this study. One group of each strain served as control animals, and another group of each strain underwent volume expansion with saline (5% of body weight infused during a period of 30 minutes). The levels of ET-1 and ET-3 were measured in plasma by using a double-antibody radioimmunoassay. In the control groups of SHR and WKY rats, plasma ET-1 levels were 72.5 +/- 14.9 pg/ml (N = 8) and 40.2 +/- 7.5 pg/ml (N = 12), respectively (P < 0.05). In the volume-expanded SHR group (N = 8), the plasma ET-1 level was 45.5 +/- 11.1 pg/ml (approximately 37% less than that of the control SHR group), whereas it was 40.6 +/- 10.2 pg/ml in the volume-expanded group of WKY rats (N = 10) (almost identical to that of the control WKY group). Plasma levels of ET-3 were similar in control and in volume-expanded groups of SHR and WKY rats. These data show that basal levels of plasma ET-1 are significantly higher in the SHR than in the WKY rat.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased plasma level of endothelin-1 in the Okamoto spontaneously hypertensive rat. 841 54

A newly synthesized ET(A)-selective antagonist, BQ-123, was examined with respect to its anti-endothelin(ET) action in vitro and in vivo and its effect on blood pressure in Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP). In isolated porcine coronary arteries, BQ-123 (0.07 microM to 6.0 microM) shifted the concentration-response curve for ET-1 to the right without affecting the maximal response of ET-1, its pA2 value being 7.35. Intravenous infusion of BQ-123 at a rate of 1.2 and 30 mg/kg/hr produced a significant decrease in blood pressure in 20- to 29-week-old SHRSP, but did not alter blood pressure in 13- to 16-week-old WKY or in 18- to 19-week-old and 40-week-old SHR. The hypotensive effect of BQ-123 depended on the pretreatment blood pressure level. These results suggest that ET-1 is involved in part in the maintenance of high blood pressure in malignant hypertension, as exemplified by SHRSP.
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PMID:Antihypertensive effect of a newly synthesized endothelin antagonist, BQ-123, in a genetic hypertensive model. 844 1

The correction of anemia in end stage renal disease with recombinant human erythropoietin (rHuEPO) is associated with hypertension in about a third of hemodialysis patients. In the present study, we investigated the role of endothelin (ET-1) on rHuEPO associated hypertension and the effect of the rHuEPO administration route on plasma ET-1 levels. We studied 50 stable chronic hemodialysis patients who were divided into three groups: 26 patients received rHuEPO intravenously (IV) and 21 subcutaneously (SC). The control group was nine patients who were treated with nandrolone decanoate (ND). Prehemodialysis ET-1 plasma levels were correlated with mean arterial pressure (MAP), hematocrit (Hct), time on dialysis, and rHuEPO doses. The antihypertensive therapeutic index (ATI) was used to determine the changes in blood pressure medication intake. We observed that the ET-1 levels were significantly higher in the IV group (19.3 +/- 2) than the SC (5.0 +/- 0.6) or ND groups (3.6 +/- 0.4 pg/mL) (P < 0.001, IV v SC or ND). After IV rHuEPO treatment, there were increases in both MAP (pre- v post-rHuEPO, P < .001) and in ATI (pre- v post-rHuEPO, P < .001). In the SC group, the increases in MAP and ATI were not significant. Only the IV group showed a significant correlation between MAP and ET-1 levels (r = .05, P = .02). To accomplish the same Hct, the IV group received higher rHuEPO doses than those of the SC (180 +/- 15 v 87 +/- 12 U/kg/week) (P < .001). No significant correlations were found between the plasma ET-1 levels and Hct, time on dialysis and rHuEPO doses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intravenous erythropoietin (rHuEPO) administration increases plasma endothelin and blood pressure in hemodialysis patients. 847 Dec 28

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

An alteration in renal metabolism of endothelin may contribute to hypertension in the SHR and it has been shown that the excretion rate of endothelin is reduced in patients with essential hypertension. We measured plasma and urinary endothelin 1 (ET-1) in 20 untreated essential hypertensives with normal renal function, in eight normotensive healthy subjects, and in 13 hypertensive patients with primary renoparenchymal disease. Plasma ET-1 was higher (P < 0.01) in essential hypertensives (median 1.69, interquartile range 1.2-3.3 pg/ml) than in normal subjects (0.84, 0.37-1.10 pg/ml) but significantly less (P < 0.01) than in hypertensives with renoparenchymal disease (3.57, 1.45-9.52 pg/ml). ET-1 levels slightly correlated with diastolic pressure in essential hypertensives (r = 0.43, P < 0.05) and tended to be correlated with systolic pressure in hypertensives with renal disease (r = 0.47, P = 0.08). ET-1 excretion in essential hypertensives (137, 99-154 ng/24 h) and in normal subjects (120, 62-150 ng/24 h) was significantly lower than in renal hypertensives (191, 123-241 ng/24 h). The ET clearance/GFR ratio (ClET/GFR) was markedly reduced (30%, 21-67%) in essential hypertensives and substantially raised in renal hypertensives (164%, 86-314%) in comparison with normal subjects (83%, 35-94%). Since the ClET/GFR ratio should be 100% if all filtered ET-1 is excreted, the data indicate that ET-1 is synthesized at a reduced rate and/or broken down at an enhanced rate by the kidney in essential hypertension and confirm that there is a high ET-1 generation rate in remnant nephrons in hypertension secondary to renal disease.
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PMID:Urinary and plasma endothelin 1 in essential hypertension and in hypertension secondary to renoparenchymal disease. 853 21

1. Hypertensive transgenic (TGR(mRen-2)27) (abbreviated to TG) rats (n = 6) and their normotensive Sprague-Dawley (SD) control strain (n = 7) were chronically instrumented for the measurement of cardiac haemodynamics. The hypertension in TG rats (mean blood pressure 181 +/- 9 mmHg) was entirely attributable to a reduction in total peripheral conductance (TG rats = 169 +/- 7, SD rats = 292 +/- 15 microliters min-1 mmHg-1 100g-1) since cardiac index was not different in the two strains (TG rats = 30.5 +/- 1.2, SD rats = 29.5 +/- 1.6 ml min-1 100g-1). 2. In other animals instrumented for the assessment of regional haemodynamics, the extent of peripheral vasoconstriction was similar in renal, mesenteric and hindquarters vascular beds in the TG rats (reduction in vascular conductance relative to SD rats = 42%, 46% and 49%, respectively). 3. During an 8 h observation period with saline infusion, or following injection of losartan (10 mg kg-1) in SD rats there was no hypotension or regional vasodilation. With infusion of the endothelin antagonist, SB 209670 (10 micrograms kg-1 min-1), there was a slight hypotension, but no significant vasodilation; co-administration of losartan and SB 209670 caused a similar profile of effect, although the hypotension was increased. 4. With the same experimental protocol in TG rats, losartan caused a biphasic, progressive fall in mean arterial blood pressure accompanied by renal, mesenteric and hindquarters vasodilation. Although the response to SB 209670 was not biphasic, its hypotensive and vasodilator effects were not different from those of losartan after 8 h. In the combined presence of losartan and SB 209670, mean arterial blood pressure (116 +/- 5 mmHg) was significantly lower than with SB 209670 (132+/-4 mmHg) or losartan(136 +/- 6 mmHg) alone, and renal, mesenteric and hindquarters vascular conductances (61 +/- 3, 90+/-14 and 52+/-4 [kHz nmHg-1]103, respectively) were higher than the corresponding values following either SB 209670 (49 +/- 4, 52 +/- 4 and 34 +/- 3 [kHz mmHg- 1]103, respectively) or losartan (43 +/- 5, 59 +/- 13 and 35+/-4 [kHz mmHg-1]103, respectively) alone. These results indicate the maintenance of hypertension inTG rats is dependent upon renal, mesenteric and hindquarters vasoconstriction, mediated by angiotensinII (AII) and endothelin (ET). Since we found that plasma ET-1 levels in TG rats (12.06+/-2.87 pmol 1-1)were lower than in SD rats (21.53 +/- 3.94 pmol 1-1), then it is possible that locally-generated, rather than circulating ET-l contributes to the widespread vasoconstriction in TG rats.
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PMID:Haemodynamic effects of losartan and the endothelin antagonist, SB 209670, in conscious, transgenic ((mRen-2)27), hypertensive rats. 856 54

Microinjection of N-methyl-D-aspartate (NMDA) (0.068 to 6.8 nmol) into the periaqueductal gray area (PAG) of anaesthetized rats caused dose-dependent increases in blood pressure. Preinjection (10 min before) of FR 139317 (an ETA receptor selective antagonist; 5 nmol) or SB 209670 (an ETA/ETB receptor non-selective antagonist; 5 nmol) to the PAG reduced the pressor response to NMDA whereas BQ-788 (an ETB receptor selective antagonist; 5 nmol) did not affect the NMDA-induced hypertension. Pretreatment with DL-2-amino-5-phosphono valeric acid (2-APV) (an NMDA receptor selective antagonist, 5 nmol) also abolished the pressor response induced by NMDA. Dose-dependent increases in blood pressure induced by injection of angiotensin II (0.1-10 nmol) to the PAG were unaffected by FR 139317 or SB 209670. Thus, our data indicate that endogenous ET-1, via an action on ETA receptors, contributes to the pressor effects of NMDA within the brain.
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PMID:Involvement of endothelin in the pressor response following injection of NMDA to the periaqueductal gray area of rats. 868 Jul 7


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