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)

Studies on fibronectin, endothelin-1, and mortalin from our laboratory are reviewed here. Fibronectin expression has been analyzed as upregulated during in vitro serial passaging of human fetal lung and neonatal foreskin fibroblasts as well as umbilical vein endothelial cells. In vivo aging of skin fibroblasts, as well as aortic endothelial cells, are also accompanied by upregulation of fibronectin expression. Fibronectin promoter binding proteins from young and old cell nuclear extracts were further explored by gel retardation assay. Preliminary analyses have detected age-related differential binding activities with respect to AP-1, CRES, TFIID, CTF, and AP-2 regions, whereas Sp1 binding proteins remain unaltered. Endothelin-1 expression is also seen as upregulated during in vitro and in vivo aging of endothelial cells. This can contribute to the hypertension commonly observed in elderly patients. Mortalin, a novel member of hsp 70 family of proteins, was initially identified by virtue of its association with a cellular mortal phenotype. Subsequently, normal cells and the ones with an immortal phenotype have been found to have differential subcellular localization of this protein. Antiproliferative activity of this protein in normal cells and the deregulation of expression in transformed cells is observed which suggests the association of mortalin in pathways that determine cellular divisional phenotype.
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PMID:Expression of endothelin, fibronectin, and mortalin as aging and mortality markers. 908 6

Endothelin-1 (ET-1), a novel 21-amino acid vasoconstrictive peptide secreted by endothelial cells, has been thought to play a role in various forms of vascular disease. Diabetes mellitus is well known for its association with microvascular damage. To investigate whether ET-1 levels may be related to microangiopathy in diabetes mellitus, plasma ET-1 levels were measured in two groups of diabetic patients: A) 47 patients with non-insulin dependent diabetes mellitus (NIDDM) and retinopathy (28 M, 19 F; mean age 60.7+/-8.5 yrs) but without nephropathy (microalbuminuria < 30 mg/day) and hypertension (SBP < 140, DBP < 90 mmHg); group A was divided in three subgroups based on the severity of retinopathy: a) 16 with background retinopathy; b) 21 with pre-proliferative retinopathy; c) 10 with proliferative retinopathy. B) 8 patients with insulin-dependent diabetes mellitus (IDDM) recently diagnosed (6 M, 2 F; 16.4+/-3.8 yrs) without complications. C) 28 healthy subjects (HS) (16 M, 12 F; 47.8+/-11.8 yrs) as controls. In the NIDDM group the ET-1 concentration was significantly higher (17.3+/-2.4 pg/ml) than both in the HS (8+/-4.7 pg/ml) and IDDM patients (10.2+/-3.7 pg/ml) (p < 0.0001). In the subgroups with retinopathy the ET-1 levels were a) 15.1+/-4.3 pg/ml; b) 22.2+/-6.8 pg/ml and c) 16.6+/-5.1 pg/ml. These values were significantly elevated as compared to HS (p<0.001; p < 0.0001; p < 0.002, respectively), being the highest levels of ET-1 observed in the NIDDM patients with pre-proliferative retinopathy. In conclusion our study revealed that the ET-1 concentrations are elevated in NIDDM patients with retinopathy especially in those patients with pre-proliferative retinopathy.
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PMID:Circulating endothelin-1 in non-insulin-dependent diabetic patients with retinopathy. 922 11

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide derived from endothelial cells and may be important in the control of systemic blood pressure (BP) and local blood flow. Immunoreactive ET-1 plasma levels may be normal or elevated in human arterial hypertension, although the exact pathophysiological role of ET-1 remains to be established. The aim of our study was to determine the relationship between the components of the renin-angiotensin-aldosterone system and plasma ET-1 levels in patients with low, normal or high-renin essential hypertension. The study groups included 13 patients with low-renin essential hypertension (average age 43.5 +/- 16.2 years), 16 patients with normal-renin essential hypertension (46.5 +/- 13.4 years), 11 patients with high-renin essential hypertension (40.7 +/- 13.8 years) and 12 healthy subjects (43.1 +/- 11.4 years). Our results demonstrated that the mean ET-1 values of all patients with essential hypertension were 10.4 +/- 3.4 pg/ml; there was not a statistical correlation between plasma renin activity (PRA) and the ET-1 levels of hypertensives; instead there was a statistically significant correlation between plasma ET-1 and plasma aldosterone (PA) (r = 0.393; P < 0.026). In particular mean plasma ET-1 values in patients with low-renin essential hypertension (12.6 +/- 2.1 pg/ml) were significantly higher (ANOVA = 0.000, P < 0.05) than those of normotensive subjects (7.7 +/- 1.7 pg/ml), patients with normal-renin essential hypertension (8.5 +/- 2.8 pg/ml), and patients with high-renin essential hypertension (9.9 +/- 3.8 pg/ml), respectively. There was a statistical correlation between PA and ET-1 levels in patients with low-renin essential hypertension (r = 0.619, P < 0.024). Our study demonstrated that there was an increase of circulating ET-1 levels in patients with low-renin essential hypertension and ET-1 plasma levels correlated with PA. The results suggest that ET-1 may play an important role in this particular form of human essential hypertension.
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PMID:High plasma endothelin-1 levels in hypertensive patients with low-renin essential hypertension. 928 62

Cadmium administered intraperitoneally at a dose of 1 mg/kg/day for 15 days caused a significant increase in mean arterial blood pressure. Endothelin-1 and noradrenaline produced concentration-dependent contractions of aortic rings that attained a lower maximal contraction in cadmium-injected rats as compared with control rats (p < 0.05). On the other hand, responses of aortic rings to different concentrations of potassium chloride did not show a significant difference between the groups. The decreased responsiveness of the aortae of cadmium-hypertensive rats to endothelin-1 and noradrenaline could either be due to an interaction of cadmium with receptors or intracellular signal transduction pathways of these agents, or it may simply reflect the adaptive changes in vascular tissues following hypertension development.
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PMID:Responsiveness of aortic rings of cadmium-hypertensive rats to endothelin-1. 928 17

Endothelin-1 (ET-1) is formed from its precursor preproET-1 via the cleavage of the intermediate bigET-1 by endothelin-converting enzyme (ECE-1). However, the subcellular site at which this step occurs is not clear: It could occur intravesicularly along the secretory pathway or bigET-1 might be released and processed extracellularly. To address this point, we have developed an integrated autocrine system that uses a recombinant Chinese hamster ovary (CHO) luciferase reporter cell line that permanently expresses the human ET(A) receptor. Into these cells we transiently transfected human ECE-1a cDNA, either together with the human preproET-1 cDNA (as an endogenous source of bigET-1), or alone (in which case exogenous bigET-1 was added). Phosphoramidon inhibited the conversion of exogenous bigET-1 (IC50 = 5 to 30 micromol/L) much better than that of endogenous bigET-1 (IC50 > 1 mmol/L). Both conversions showed similar high yields (20% to 100%) that depended on the amount of ECE-1a expressed. Thus, ECE-1a has two equally relevant activities in this recombinant system for CHO cells: (1) an intracellular, probably intravesicular activity, corresponding to the ECE-1a-mediated step of ET-1 biosynthesis and (2) an extracellular activity at the plasma membrane. If this is also the case for endothelial cells, ECE-1a inhibitors would have to cross the plasma and vesicle membranes to be effective. The present system could be useful for screening such inhibitors.
Hypertension 1997 Oct
PMID:A live-cell assay for studying extracellular and intracellular endothelin-converting enzyme activity. 933 81

The effect of parathyroid hormone-related protein on interleukin-1beta-induced nitric oxide production was studied in rat vascular smooth muscle cells. Interleukin-1beta time- and dose-dependently enhanced the production of nitrite, a stable metabolite of nitric oxide. Parathyroid hormone-related protein(1-34) alone up to 10(-7) mol/L had no obvious effect, but significantly increased the cytokine-induced nitrite production. RNA analysis revealed that the synergistic effect of parathyroid hormone-related protein(1-34) resulted from a potentiation of the expression of inducible nitric oxide synthase and GTP-cyclohydrolase I, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which is a cofactor of nitric oxide synthase. The increased nitric oxide release induced by interleukin-1beta or interleukin-1beta with parathyroid hormone-related protein(1-34) was completely inhibited by coincubation with 3x10(-3) mol/L N(G)-monomethyl-L-arginine, a competitive inhibitor of nitric oxide synthase, or with 10(-3) mol/L 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP-cyclohydrolase I. Endothelin-1 potentiated interleukin-1beta induction of nitric oxide, which might be mediated by endogenous parathyroid hormone-related protein. Neutralization of exogenous or endogenous parathyroid hormone-related protein with antibody attenuated the synergistic effect of parathyroid hormone-related protein, but did not affect interleukin-1beta induction of nitric oxide. These results suggest that locally produced parathyroid hormone-related protein acts as a synergistic regulator upregulating interleukin-1beta-induced nitric oxide synthesis in the cardiovascular system, and thereby may affect vascular tone and/or vascular remodeling after vascular injury in some pathological processes such as atherosclerosis and hypertension.
Hypertension 1997 Oct
PMID:Parathyroid hormone-related protein upregulates interleukin-1beta-induced nitric oxide synthesis. 933 94

Endothelin-1 (ET-1), an endothelium-derived vasoactive peptide, functions as a potent vasoconstrictor as well as mitogen. We show here a novel role for ET-1 as an apoptosis survival factor for cultured rat endothelial cells. When we rendered endothelial cells obtained from rat aorta quiescent by serum starvation, significant portions of cultured cells underwent apoptotic death as demonstrated by nucleosomal laddering on agarose gel electrophoresis, flow cytometry analysis with FACS, and the TdT-mediated dUTP biotin nick-end labeling (TUNEL) method. ET-1 dose-dependently (10[-12] to 10[-6] mol/L) suppressed the apoptosis induced by serum starvation. The ET(B) receptor antagonist (BQ788; 10[-6] mol/L) and ET(A/B) receptor antagonists (PD142893 and PD145065; 10[-6] mol/L), but not the ET(A) receptor antagonist (BQ123; 10[-6] mol/L), blocked the apoptosis protective effect of 10[-7] mol/L ET-1. Nonimmune rabbit serum reduced the apoptotic event induced by serum deprivation, whereas neutralization of endogenous ET-1 by polyclonal anti-ET-1 antiserum abrogated this protective effect. The ET(B) receptor antagonist (BQ788; 10[-8] to 10[-6] mol/L), but not the ET(A) receptor antagonist (BQ123; 10[-8] to 10[-6] mol/L), significantly inhibited proliferation of endothelial cells. These data suggest that ET-1, as well as mitogen, functions as an apoptosis survival factor for endothelial cells in an autocrine/paracrine manner via the ET(B) receptor.
Hypertension 1997 Nov
PMID:Endothelin-1 as an autocrine/paracrine apoptosis survival factor for endothelial cells. 936 76

Endothelin-1 (0.25 nmol/kg, injected into the left cardiac ventricle) induces a protracted increase of mean arterial pressure that is significantly reduced by the selective ET(A) receptor antagonist BQ-123 (1 and 10 mg/kg) in the anesthetized rabbit. The sole administration of the selective ET(B) antagonist BQ-788 (0.25 mg/kg) induces a pressor response abolished by BQ-123 (1 mg/kg). Concomitant to the increase in mean arterial pressure, BQ-788 induces a significant increase in plasma levels of endothelin-1 and its precursor big endothelin-1. The nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) also increases arterial blood pressure, and the response is reduced dose-dependently by BQ-123 (1 and 10 mg/kg). In addition, the administration of BQ-788 in the presence of L-NAME induced a further increase in arterial blood pressure. The duration of the pressor response to L-NAME is also significantly reduced by an endothelin-converting enzyme inhibitor, phosphoramidon (10 mg/kg). Finally, L-NAME induces an increase in plasma levels of big endothelin-1 but not endothelin-1. Our results illustrate that blockade of either nitric oxide synthase or ET(B) receptors triggers a raise in plasma levels of endothelin-1 or its precursor. These later moieties are suggested to be significantly involved, through the activation of ET(A) receptors, in the pressor effects of L-NAME and BQ-788 in the anesthetized rabbit.
Hypertension 1997 Nov
PMID:ET(B) receptor and nitric oxide synthase blockade induce BQ-123-sensitive pressor effects in the rabbit. 936 77

Plasma concentration of endothelin-1, a potent vasoconstrictor produced by the vascular endothelium, has been observed to be significantly increased in a number of pathophysiological states, including preeclampsia. In the present study we have evaluated the effects of elevated plasma endothelin-1 in pregnant sheep by continuous exogenous endothelin-1 administration. Nine pregnant ewes (110+/-5 days' gestation) were instrumented for measurements of maternal mean arterial pressure, renal blood flow, and uterine blood flow. After recovery, endothelin-1 was infused intravenously for 4 hours at a dose that was adjusted to raise mean arterial pressure by approximately 20 mm Hg by the end of the first hour (range 5 to 20 ng/kg per minute). Mean arterial pressure, renal blood flow, uterine blood flow, urinary protein excretion, hematocrit, and plasma endothelin-1 concentration were measured hourly, and renal and uterine vascular resistances were calculated. Endothelin-1 produced significant increases (% change from baseline at t=4 hours) in mean arterial pressure (45+/-8%), renal vascular resistance (353+/-66 %), and uterine vascular resistance (59+/-21%). Endothelin-1 also increased microvascular permeability both systemically and within the kidney, as suggested by marked increases in hematocrit (0.27+/-0.01 to 0.32+/-0.01) and urinary protein concentration (0.95+/-0.1 to 7.9+/-3.2 mg/mL per mg creatinine). There was a highly significant correlation (P<.0001) between plasma endothelin-1 and mean arterial pressure, renal vascular resistance, uterine vascular resistance, hematocrit, and urinary protein content in all sheep studied. In addition, plasma endothelin-1 corresponded well with the time course of the changes in cardiovascular parameters and urinary protein excretion observed. These results provide evidence to suggest that elevation of circulating endothelin-1 in pregnant sheep can produce cardiovascular and hemodynamic changes that in many ways resemble the human disease preeclampsia. This supports the hypothesis that endothelial cell damage and/or dysfunction that is associated with increased production of endothelin-1 could directly contribute to the progression of preeclampsia.
Hypertension 1997 Dec
PMID:Effects of continuous infusion of endothelin-1 in pregnant sheep. 940 87

Abnormal renal handling of water and sodium is implicated in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). Alteration of renal endothelin-1 synthesis is also reported in SHR. Endothelin-1, a potent vasoconstrictor and regulator of sodium reabsorption in the nephron, has a pathophysiological potential in the development of hypertension. Because synthesis of bioactive endothelin-1 requires endothelin converting enzyme-1 (ECE-1), we investigated whether renal ECE-1 gene expression is altered in the kidney of SHR. Kidneys from both 4- and 12-week-old SHR and age-matched Wistar-Kyoto rats (WKY) were studied. ECE-1 mRNA in microdissected nephron segments was assessed by reverse transcription-competitive polymerase chain reaction, and ECE-1 protein level by Western blot. In 4-week-old SHR, ECE-1 mRNA was significantly increased in the proximal straight tubule, medullary thick ascending limb, cortical thick ascending limb, and inner medullary collecting duct. ECE-1 protein level was increased in both the outer and inner medulla. In 12-week-old SHR, ECE-1 gene expression was significantly increased in the proximal straight tubule, medullary thick ascending limb, and also in the glomeruli. Glomerular preproendothelin-1 mRNA expression was not different between the two strains at both 4 and 12 weeks. We conclude that high ECE-1 gene expression in the nephron, via increase of endothelin-1 synthesis, may promote sodium retention that contributes to the development and/or maintenance of hypertension in SHR.
Hypertension 1997 Dec
PMID:Endothelin converting enzyme-1 gene expression in the kidney of spontaneously hypertensive rats. 940 88


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