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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eight Na-repleted volunteers underwent 3 separate 90-minute infusions of either N(G)-nitro-L-arginine methyl ester (L-NAME) 3.0 mg. kg(-1). min(-1) or endothelin-A receptor (ET-A) blocker BQ-123 (BQ) 0.125 nmol. kg(-1). min(-1) or both. Mean arterial pressure (MAP), glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistances (RVR), and sodium excretion rate (UNaV) were measured at baseline (b) and from 0 to 45 minutes (period 1) and 45 to 90 minutes (period 2) of infusion. BQ alone had no effect. GFR declined by 4.9% (P<0.001 versus b) in period 1, to 9.9% (P<0. 001) in period 2 with L-NAME, and by 3.3% (P<0.01) to 6.6% (P<0.001) with L-NAME plus BQ (P=NS between L-NAME and L-NAME plus BQ). UNaV fell equally with L-NAME or L-NAME plus BQ. MAP rose significantly in period 2 with L-NAME (6.9%; P<0.001) but not with coinfused BQ (2. 1%; P=NA versus b, P=0.005 versus L-NAME alone). RBF declined by 12. 2% (P<0.001) to 18.3% (P<0.001) with L-NAME and by 4.6% (P<0.005) to 8.2% (P<0.001) with L-NAME plus BQ. These changes were smaller with L-NAME plus BQ (P<0.05 in period 1 and P<0.02 in period 2). Blunted changes were also seen for RVR (P<0.005 in period 1 and P<0.001 in period 2 between L-NAME alone and L-NAME plus BQ). These findings show that systemic and renal vasoconstriction due to L-NAME are attenuated by BQ, which suggests that an interaction between endogenous nitric oxide production and ET-A activity participates in the maintenance of baseline systemic and renal vascular tone in humans.
Hypertension 2000 Jan
PMID:Endothelin-A blockade attenuates systemic and renal hemodynamic effects of L-NAME in humans. 1064 52

To investigate the hypothesis that high blood pressure activates the endothelin system in the vessel wall, isolated segments of the rabbit carotid artery were subjected to different levels of perfusion pressure. Both preproendothelin-1 (ppET-1) mRNA abundance and intravascular ET-1 peptide content were strongly upregulated on raising the intraluminal pressure from 90 to 160 mm Hg for 3 to 12 hours, and this increase in ppET-1 mRNA occurred predominantly in the endothelial cells. Endothelin-converting enzyme-1 and endothelin A receptor (ET(A)-R) expression were pressure-insensitive, whereas that of the ET(B)-R in the smooth muscle cells was also significantly enhanced. Both the pressure-induced increase in ppET-1 and ET(B)-R expression required RNA synthesis because they were abolished by actinomycin D. The nuclear signaling mechanisms involved therein, however, appeared to be different. Thus, the pressure-induced expression of ppET-1 and activation of CCAAT-enhancer binding proteins beta and delta were blocked by the tyrosine kinase inhibitor herbimycin A, whereas ET(B)-R expression and the nuclear translocation of activator protein-1 were abolished by the protein kinase C inhibitor Ro 31-8220. One consequence of these presumably deformation-induced changes in gene expression was an increased rate of apoptosis of the smooth muscle cells in the media that if transferable to the situation in human blood vessels may contribute to hypertension-induced arterial remodeling.
Hypertension 2000 Feb
PMID:Elevated perfusion pressure upregulates endothelin-1 and endothelin B receptor expression in the rabbit carotid artery. 1067 12

Endothelin (ET) -1 is a potent vasoconstrictor and promitogenic peptide produced by the vascular endothelium. The ET system is activated in atherosclerosis and in most cardiovascular conditions associated with increased vascular tone and remodelling. There are two ET-receptor (ET-R) subtypes: the ETA-Rs mediate smooth muscle vasoconstriction and proliferation, and the more complex ETB-Rs have antagonistic actions - they serve a dual role of clearance and vasodilation in the endothelium, while in smooth muscle cells they also provoke vasoconstriction. Selective ETA-R and nonselective ETA/B-R antagonists are entering the clinical development phase. These agents have shown their effectiveness in the therapy of various models of heart failure, pulmonary hypertension, systemic hypertension and ischemia-reperfusion and in the prevention of restenosis. In patients with congestive heart failure, short term ET-antagonist (ET-R) therapy provides hemodynamic and symptomatic improvement. Because of the dual role of the ETB-R, nonselective antagonists may provide greater or fewer benefits than selective ETA-R antagonists: a lack of direct comparison of the two categories of agents, however, does not allow this distinction at present. In the evaluation of this new class of therapeutic agents, particular attention should be paid to potency and receptor selectivity of a compound, the alterations in ETA-R and ETB-R activity brought on by pathological conditions, the proportions of ETA versus ETB-R of the target system, and finally, the net importance of the possible protective role of the endothelial ETB versus the deleterious effects of the smooth muscle ETB-R.
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PMID:Endothelin receptor antagonists and their developing role in cardiovascular therapeutics. 1093 9

The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA) compared with combined endothelin A/B receptor antagonism (ETA/B-RA); and third, to assess whether interruption of both RAS and endothelin system had any advantages over single-system blockade. Subtotally nephrectomized rats were studied as a model of progressive renal injury and randomly assigned to one of the following treatments for 12 weeks: perindopril (ACE inhibitor), irbesartan (AT1 receptor antagonist), BMS193884 (ETA-RA), bosentan (ETA/B-RA), and a combination of irbesartan with either perindopril or BMS193884. Treatment with irbesartan or perindopril was associated with an improved glomerular filtration rate and reductions in blood pressure, urinary protein excretion, glomerulosclerosis, and tubular injury in association with reduced gene expression of transforming growth factor-beta(1) and matrix protein type IV collagen. The combination of irbesartan with perindopril was associated with further reductions in blood pressure and urinary protein excretion. No beneficial effects of either BMS193884 or bosentan were noted. Furthermore, the addition of BMS193884 to irbesartan did not confer any additional benefits. These findings suggest that the RAS but not the endothelin system is a major mediator of progressive renal injury after renal mass reduction and that the combination of an AT1 receptor antagonist with an ACE inhibitor may have advantages over the single agent of RAS blocker treatment.
Hypertension 2000 Oct
PMID:Blockade of the renin-angiotensin and endothelin systems on progressive renal injury. 1135 55

We evaluated the effects of cilnidipine, a long-acting Ca(2+) channel antagonist, on endothelial nitric oxide synthase (eNOS), preproendothelin-1 and endothelin ETA receptor expression in the left ventricle, and evaluated the relations between these effects and coronary microvascular remodeling and extracellular signal-regulated kinases belonging to one subfamily of mitogen-activated protein kinases in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Cilnidipine (DOCA-cilnidipine, 1 mg/kg/day, subdepressor dose) or vehicle (DOCA-vehicle) was given after induction of DOCA-salt hypertension for 5 weeks. The eNOS mRNA and protein expression in the left ventricle was significantly lower in DOCA-vehicle than in control rats and significantly higher in DOCA-cilnidipine than in DOCA-vehicle rats. Preproendothelin-1 and endothelin ETA receptor expression levels and phospho-p42/p44 extracellular signal-regulated kinase activities were significantly increased in DOCA-vehicle compared with control rats and significantly suppressed in DOCA-cilnidipine compared with DOCA-vehicle rats. DOCA-vehicle rats showed a significant increase in the wall-to-lumen ratio, perivascular fibrosis and myocardial fibrosis, with all these parameters being significantly improved by cilnidipine. These results led us to conclude that phospho-p42/p44 extracellular signal-regulated kinase activities may contribute to the coronary microvascular remodeling of DOCA rats and that protective effects of cilnidipine on cardiovascular remodeling may be at least in part mediated by an increased eNOS expression and a decreased endothelin-1 and endothelin ETA receptor expression in the left ventricle.
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PMID:Effects of cilnidipine on nitric oxide and endothelin-1 expression and extracellular signal-regulated kinase in hypertensive rats. 1143 Sep 25

Endothelin-1 has potent vasoconstrictor and vasopressor actions contributing to basal vascular tone and maintenance of blood pressure acting predominantly through endothelin-A receptors. Endothelin antagonists may be of value in the treatment of hypertension and heart failure. However, the role of endothelin-1 in the regulation of vascular tone and the potential benefits of endothelin antagonists in non-insulin-dependent diabetes mellitus (Type II diabetes) are less clear. Vasoconstriction to exogenous endothelin-1 is impaired in Type II diabetes. The purpose of this study was to determine whether vasoconstriction to endogenous endothelin-1 acting through the endothelin-A receptor is impaired in Type II diabetes. In ten patients with Type II diabetes and nine controls the endothelin-A receptor antagonist BQ123 was infused intra-arterially at 100 nmol/min for 60 min followed by normal saline for 30 min. Forearm blood flow was measured using venous occlusion plethysmography. Control subjects showed gradual onset of vasodilation in response to BQ123 (P < 0.001). Diabetic subjects, however, showed no significant response (P > 0.05). There was a significant difference between the diabetic and control groups (P < 0.05). Blockade of the endothelin-A receptor is associated with impaired vasodilation in Type II diabetes indicating vasoconstriction to endogenous endothelin-1 mediated by the endothelin-A receptor is impaired.
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PMID:Vasoconstriction to endogenous endothelin-1 is impaired in patients with type II diabetes mellitus. 1178 68

Pharmacological antagonism of the endothelin system presents a novel target for the treatment of a range of cardiovascular diseases. The antagonists developed so far differ in their endothelin receptor subtype specificity. Indeed, at present there is no consensus opinion as to what level of receptor selectivity defines a particular antagonist as 'selective' or 'mixed'. Antagonists that are highly selective for the endothelin A receptor (ETA) receptor subtype have a number of hypothetical advantages over non-selective antagonists. This theory is based on the analysis of the function of the endothelin B (ETB) receptor. Current evidence suggests that activation of the ETB receptor results in vasodilatation, diuresis and natriuresis, each of which are properties that might be advantageous to maintain in conditions such as cardiac failure and hypertension. However, definitive evidence to suggest a therapeutic advantage of selective ETA receptor antagonists requires long-term, head-to-head studies to be performed.
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PMID:Are selective endothelin A receptor antagonists better than mixed antagonists? 1181 76

This study hypothesizes that endothelin-1 induces renal damage by increasing expression of growth/inflammatory factors, important in renal fibrosis. Male stroke-prone spontaneously hypertensive rats (SHRSPs) (8-weeks, n = 24) were randomized into three groups: control group, high-salt group (4% NaCl), and salt plus an endothelin A receptor antagonist, BMS 182874 (40 mg/kg/d). After 20 weeks treatment, rats were killed. Messenger RNA (mRNA) expression of renal preproendothelin-1, endothelin A and B receptors, and procollagen I and III was evaluated by reverse transcription polymerase chain reaction. Expression of transforming growth factor (TGF)-beta1 and basic fibroblast growth factor (bFGF) was determined by immunoblotting. Matrix metalloproteinase-2 (MMP-2) activity was measured by zymography. In salt-loaded SHRSPs, preproendothelin-1 mRNA expression was increased 1.6-fold, and endothelin A receptor mRNA expression was decreased (70% of control). Salt-loaded SHRSPs had increased renal expression of TGF-b1 and procollagens. MMP-2 activity was augmented fivefold. BMS decreased (p < 0.01) expression of TGF-beta1, bFGF, and procollagen I and reduced MMP-2 activity. Thus severe hypertension and renal dysfunction in salt-loaded SHRSPs are associated with increased expression of renal endothelin-1, growth factors, and collagen. BMS treatment alleviated these effects, suggesting that nephroprotection by endothelin A receptor blockade is mediated by normalizing expression of growth factors, reducing extracellular matrix deposition, and decreasing MMP activity.
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PMID:Endothelin A receptor blockade decreases expression of growth factors and collagen and improves matrix metalloproteinase-2 activity in kidneys from stroke-prone spontaneously hypertensive rats. 1202 84

Although insulin-mediated vasodilation is impaired in insulin resistance, the mechanisms of this are unknown. We investigated factors mediating vasoactive responses to insulin in control and insulin-resistant rats. Responses to insulin in small mesenteric arteries from control and insulin-resistant rats were investigated after blocking endothelin-A receptors, cyclooxygenase, nitric oxide synthase, and potassium channels. In addition, insulin's effect on prostacyclin production in small mesenteric blood vessels was assessed by enzyme immunoassay. Insulin induced a concentration-dependent vasodilation in control arteries that was absent in arteries from insulin-resistant rats. However, in the presence of BQ610, an endothelin-A receptor antagonist, the response to insulin was normalized in insulin-resistant arteries. In control arteries, insulin-induced vasodilation was completely inhibited by indomethacin, meclofenamate, glibenclamide, or potassium chloride. In contrast, neither n-nitro-L-arginine nor the combination of charybdotoxin and apamin altered vasodilation to insulin. In insulin-resistant arteries in the presence of BQ610, vasodilation was also inhibited by indomethacin, glibenclamide, and potassium chloride. Insulin increased prostacyclin production in small mesenteric blood vessels from both groups of rats to a similar degree. Insulin-induced vasodilation in small rat mesenteric arteries is mediated through prostacyclin- and ATP-dependent potassium channels. However, insulin-resistant arteries do not vasodilate to insulin unless endothelin-A receptors are blocked. Thus, impaired relaxation to insulin in insulin-resistant rats is due to enhanced vasoconstriction by endothelin, which offsets a normal vasodilatory response to insulin.
Hypertension 2002 Jul
PMID:Enhanced endothelin activity prevents vasodilation to insulin in insulin resistance. 1246 88

Renal endothelin-1 participates in sodium and water handling, and its urinary excretion is increased in sodium-retentive states. We compared the cortical and medullary renal expression of prepro-endothelin-1, endothelin-converting enzyme-1, and endothelin type A and type B receptors in patients who underwent nephrectomy after normal (108 mmol/d NaCl; n=6) or low (20 mmol/d NaCl; n=6) sodium diet and investigated whether sodium exerts a direct role on endothelin receptor binding in vitro. With normal sodium diet prepro-endothelin-1 mRNA was 3-fold higher in renal medulla than in cortex (P<0.01), whereas endothelin-converting enzyme-1 mRNA was equally distributed. Endothelin-1 receptor density was 2-fold higher in renal medulla than in cortex (P<0.05). Type B was the main receptor subtype in both regions. In the renal cortex, low sodium diet caused a 194% increase in prepro-endothelin-1 mRNA (P<0.05), whereas endothelin-converting enzyme-1 type B and type A receptors remained unchanged. In contrast, in the renal medulla the increase in prepro-endothelin-1 mRNA (+30%, P<0.05) was associated with a selective increase in type B receptor for both mRNA expression (+37%, P<0.05) and binding density (+55%, P<0.05). Increasing in vitro sodium concentrations between 154 and 308 mmol/L significantly enhanced type B receptor density (P<0.05) and affinity (P<0.05). In conclusion, during low sodium diet, renal prepro-endothelin-1 synthesis increases mainly in the renal cortex (where no changes in receptors occur), whereas type B receptor is selectively enhanced in the renal medulla. The range of sodium concentrations that are physiologically present in vivo in the renal medulla selectively modulate type B receptor density and affinity.
Hypertension 2002 Aug
PMID:ET(B) receptor in renal medulla is enhanced by local sodium during low salt intake. 1215 10


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