Endothelin-1 inhibits endothelium-dependent vasodilatation in the human forearm: reversal by ETA receptor blockade in patients with atherosclerosis

2002 ◽  
Vol 102 (3) ◽  
pp. 321-327 ◽  
Author(s):  
Felix BÖHM ◽  
Gunvor AHLBORG ◽  
John PERNOW
Keyword(s):  
Endothelial Dysfunction ◽  
Venous Occlusion ◽  
Similar Degree ◽  
Receptor Blockade ◽  
Arterial Infusion ◽  
Endothelin 1 ◽  
Enhanced Expression ◽  
Eta Receptor ◽  
Eta Receptor Antagonist

Several cardiovascular disorders, including atherosclerosis, are associated with endothelial dysfunction and enhanced expression of endothelin-1 (ET-1). The role of ET-1 in the development of endothelial dysfunction in vivo remains unclear. The objective of the present study was to investigate the effect of elevated circulating levels of ET-1 on endothelium-dependent vasodilatation (EDV), and to test the hypothesis that ETA receptor antagonism improves EDV in patients with atherosclerosis. EDV and endothelium-independent vasodilatation were determined by brachial artery infusion of acetylcholine and sodium nitroprusside respectively during measurement of forearm blood flow (FBF) with venous occlusion plethysmography. A 60min intra-arterial infusion of ET-1 (n = 10) significantly blunted EDV in young healthy males (33±13% compared with 271±74% increase in FBF induced by 10μg/min acetylcholine; P < 0.01). Noradrenaline, which evoked a similar degree of vasoconstriction, did not attenuate EDV. In a separate set of experiments, a 60min intra-arterial infusion of the selective ETA receptor antagonist BQ123 evoked a significant increase in EDV in patients with atherosclerosis (n = 10; 109±45% compared with 255±101% increase in FBF induced by 10μg/min acetylcholine; P < 0.01), whereas no significant change was observed in healthy age-matched controls (n = 9). Endothelium-independent vasodilatation was not affected by ET-1 or BQ123. These observations demonstrate that elevated levels of ET-1 impair EDV in healthy control subjects. Furthermore, ETA receptor blockade improves EDV in patients with atherosclerosis, indicating that ET-1 attenuates EDV via an ETA-receptor-mediated mechanism.

In vitro and in vivo effects of endothelin-1 and YM598, a selective endothelin ETA receptor antagonist, on the lower urinary tract

2008 ◽  
Vol 580 (3) ◽  
pp. 394-400 ◽  
Author(s):  
Masashi Ukai ◽  
Hironori Yuyama ◽  
Akira Fujimori ◽  
Akiko Koakutsu ◽  
Masanao Sanagi ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Receptor Antagonist ◽  
Lower Urinary Tract ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
In Vivo Effects ◽  
Lower Urinary

The endothelin-1 receptor antagonist bosentan protects against ischaemia/reperfusion-induced endothelial dysfunction in humans

2005 ◽  
Vol 108 (4) ◽  
pp. 357-363 ◽  
Author(s):  
Felix BÖHM ◽  
Magnus SETTERGREN ◽  
Adrian T. GONON ◽  
John PERNOW
Keyword(s):  
Endothelial Dysfunction ◽  
Oral Administration ◽  
Receptor Antagonist ◽  
Reperfusion Injury ◽  
Venous Occlusion ◽  
Ischaemia Reperfusion Injury ◽  
Endothelin 1 ◽  
Ischaemia Reperfusion ◽  
Etb Receptor

Endothelial dysfunction may contribute to the extent of ischaemia/reperfusion injury. ET (endothelin)-1 receptor antagonism protects against myocardial ischaemia/reperfusion injury in animal models. The present study investigated whether oral administration of an ETA/ETB receptor antagonist protects against ischaemia/reperfusion-induced endothelial dysfunction in humans. FBF (forearm blood flow) was measured with venous occlusion plethysmography in 13 healthy male subjects. Forearm ischaemia was induced for 20 min followed by 60 min of reperfusion. Using a cross-over protocol, the subjects were randomized to oral administration of 500 mg of bosentan or placebo 2 h before ischaemia. Endothelium-dependent and -independent vasodilatation were determined by intra-brachial infusion of acetylcholine (1–10 μg/min) and nitroprusside (0.3–3 μg/min) respectively, before and after ischaemia. Compared with pre-ischaemia, the endothelium-dependent increase in FBF was significantly impaired at 15 and 30 min of reperfusion when the subjects received placebo (P<0.01). When the subjects received bosentan, the endothelium-dependent increase in FBF was not affected by ischaemia/reperfusion. Endothelium-independent vasodilatation was not affected during reperfusion compared with pre-ischaemia. The vaso-constrictor response induced by intra-arterial infusion of ET-1 was attenuated significantly by bosentan (P<0.001). The results suggest that the dual ETA/ETB receptor antagonist bosentan attenuates ischaemia/reperfusion-induced endothelial dysfunction in humans in vivo. Bosentan may thus be a feasible therapeutic agent in the treatment of ischaemia/reperfusion injury in humans.

Ontogeny of Big endothelin-1 effects in newborn piglet pulmonary vasculature

1993 ◽  
Vol 265 (1) ◽  
pp. H139-H145 ◽  
Author(s):  
S. Liben ◽  
D. J. Stewart ◽  
J. De Marte ◽  
T. Perreault
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Vasculature ◽  
Converting Enzyme ◽  
Endothelin 1 ◽  
Amino Acid Peptide ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
Dose Dependent

Endothelin-1 (ET-1), a 21-amino acid peptide produced by endothelial cells, results from the cleavage of preproendothelin, generating Big ET-1, which is then cleaved by the ET-converting enzyme (ECE) to form ET-1. Big ET-1, like ET-1, is released by endothelial cells. Big ET-1 is equipotent to ET-1 in vivo, whereas its vasoactive effects are less in vitro. It has been suggested that the effects of Big ET-1 depend on its conversion to ET-1. ET-1 has potent vasoactive effects in the newborn pig pulmonary circulation, however, the effects of Big ET-1 remain unknown. Therefore, we studied the effects of Big ET-1 in isolated perfused lungs from 1- and 7-day-old piglets using the ECE inhibitor, phosphoramidon, and the ETA receptor antagonist, BQ-123Na. The rate of conversion of Big ET-1 to ET-1 was measured using radioimmunoassay. ET-1 (10(-13) to 10(-8) M) produced an initial vasodilation, followed by a dose-dependent potent vasoconstriction (P < 0.001), which was equal at both ages. Big ET-1 (10(-11) to 10(-8) M) also produced a dose-dependent vasoconstriction (P < 0.001). The constrictor effects of Big ET-1 and ET-1 were similar in the 1-day-old, whereas in the 7-day-old, the constrictor effect of Big ET-1 was less than that of ET-1 (P < 0.017).(ABSTRACT TRUNCATED AT 250 WORDS)

Overexpression of endothelin-1 and enhanced growth of pulmonary artery smooth muscle cells from fawn-hooded rats

1996 ◽  
Vol 270 (1) ◽  
pp. L101-L109 ◽  
Author(s):  
M. R. Zamora ◽  
T. J. Stelzner ◽  
S. Webb ◽  
R. J. Panos ◽  
L. J. Ruff ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Sprague Dawley ◽  
Endothelin 1 ◽  
Serum Stimulation ◽  
Eta Receptor ◽  
Idiopathic Pulmonary Hypertension ◽  
Eta Receptor Antagonist

Increased production of endothelin-1 (ET-1) has been detected in lungs of fawn-hooded rats (FHR) with idiopathic pulmonary hypertension. Accelerated pulmonary artery (PA) smooth muscle cell (SMC) proliferation contributes to vascular remodeling in these rats. We hypothesized that PA SMC would be an important site of enhanced ET-1 expression in FHR lung, that these SMC would have increased growth compared with cells from a normotensive strain, and that this locally produced ET-1 would contribute to the increased growth of these cells. We found that isolated FHR PASMC overexpressed preproET-1 mRNA and produced more ET-1 peptide compared with cells from normotensive Sprague-Dawley control rats (SDR). PA SMC from FHR had increased growth compared with control cells under conditions of serum withdrawal (0.1%), submaximal serum stimulation (0.3%; a condition previously found to be required for detection of growth in response to the comitogen, ET-1), and maximal serum stimulation (10%). Enhanced growth of FHR PA SMC in the presence of 0.3% serum, but not under the other test conditions, was inhibited by the ETA receptor antagonist, BQ-123. In summary, PA SMC from rats with idiopathic pulmonary hypertension overproduce ET-1. This overproduction contributes to the enhanced growth of FHR PA SMC in the presence of 0.3% serum. These cells also possess other unique growth characteristics that are independent of ET-1. Together, these ET-1-dependent and -independent growth properties likely contribute to the hyperplasia of FHR PA SMC found in vivo.

BQ123, an ETA Receptor Antagonist, Attenuates Endothelin-1-Induced Vasoconstriction in Rat Pulmonary Circulation

1993 ◽  
Vol 22 (1) ◽  
pp. 39-43 ◽  
Author(s):  
S. T. Bonvallet ◽  
M. Oka ◽  
M. Yano ◽  
M. R. Zamora ◽  
I. F. McMurtry ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Pulmonary Circulation ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Eta Receptor Antagonist

Effect of YM598, a selective endothelin ETA receptor antagonist, on endothelin-1-induced bone formation

2006 ◽  
Vol 543 (1-3) ◽  
pp. 14-20 ◽  
Author(s):  
Akiyoshi Someya ◽  
Hironori Yuyama ◽  
Akira Fujimori ◽  
Masashi Ukai ◽  
Shinji Fukushima ◽  
...  
Keyword(s):  
Bone Formation ◽  
Receptor Antagonist ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Eta Receptor Antagonist

BQ123, an ETA-receptor antagonist, attenuates hypoxic pulmonary hypertension in rats

1994 ◽  
Vol 266 (4) ◽  
pp. H1327-H1331 ◽  
Author(s):  
S. T. Bonvallet ◽  
M. R. Zamora ◽  
K. Hasunuma ◽  
K. Sato ◽  
N. Hanasato ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Receptor Antagonist ◽  
Resistance Index ◽  
Sprague Dawley ◽  
Hypoxic Pulmonary Hypertension ◽  
Mean Pressure ◽  
Eta Receptor ◽  
Medial Wall Thickness ◽  
Eta Receptor Antagonist

To investigate the role of endothelin-1 (ET-1) in the pathogenesis of hypoxic pulmonary hypertension, we studied the effects of a recently described endothelin-receptor antagonist (ETA), BQ123, on the development of this process. Intraperitoneal osmotic pumps were placed into 8-wk-old Sprague-Dawley rats that received either saline or BQ123 (0.15 mg/h). The rats were maintained in room air normoxia or placed in a hypobaric chamber (380 Torr) for 2 wk to induce hypoxic pulmonary hypertension. There were no hemodynamic differences between normoxic rats treated with either saline or BQ123. However, treatment with BQ123 attenuated the hypoxia-induced increase in pulmonary arterial mean pressure and total pulmonary resistance index by 60 and 87% respectively. There was also a reduction in hypoxia-induced right ventricular hypertrophy in the BQ123 group. Histological studies performed using a barium-gelatin fixation technique in hypoxic BQ123-treated animals demonstrated a decrease in medial wall thickness in arteries corresponding to the respiratory and terminal bronchioles, respectively. Similarly, there was a significant reduction in the degree of muscularization of more distal vessels at the level of alveolar ducts in BQ123-treated hypoxic rats. We conclude that the ETA-receptor antagonist BQ123 attenuates the development of hypoxic pulmonary hypertension in rats in vivo, thereby suggesting a possible contributing role for ET-1 and the ETA receptor in the pathogenesis of this process.

Action of the endothelin receptor (ETA) antagonist BQ-123 on forearm blood flow in young normotensive subjects

2002 ◽  
Vol 102 (6) ◽  
pp. 661-666 ◽  
Author(s):  
R.C. WIMALASUNDERA ◽  
S.A.McG. THOM ◽  
L. REGAN ◽  
A.D. HUGHES
Keyword(s):  
Blood Flow ◽  
Vascular Tone ◽  
Forearm Blood Flow ◽  
Randomized Study ◽  
Double Blind ◽  
Eta Receptor ◽  
Normotensive Subjects ◽  
Eta Receptor Antagonist ◽  
Forearm Occlusion

Endothelin-1 (ET-1) has been proposed to contribute to the regulation of vascular tone in humans. BQ-123, an ETA receptor antagonist, has also been reported to increase forearm blood flow (FBF) in vivo; however, the efficacy of BQ-123 as an antagonist of ET-1 has not been evaluated in the forearm. The present study investigated the effects of BQ-123 on changes in FBF in response to ET-1 and noradrenaline (NA; norepinephrine), taking into account the possible influence of vasodilator effects of BQ-123 on responses to vasoconstrictors. Six subjects (age 25-34 years) participated in a double-blind randomized study. FBF was measured by forearm occlusion plethysmography. Drugs were infused intra-arterially into the non-dominant arm (study arm) on four separate occasions; the non-infused arm was used as a control. The effects of BQ-123 (50nmol/min for 60min, or 300nmol/min for 5min followed by saline for 55min) were compared with the effects of infusion of sodium nitroprusside (SNP; 12nmol/min for 60min) or saline on vasoconstriction induced by ET-1 (10pmol/min for 7min) and NA (120pmol/min for 7min). Infusion of BQ-123 at either dose did not significantly increase FBF, whereas SNP increased FBF by 134% (P = 0.03). ET-1 significantly reduced FBF, and this effect was almost completely inhibited by both doses of BQ-123, but was unaffected by SNP. NA also reduced FBF, and this action was unaffected by BQ-123 or SNP. The data show that BQ-123 is a selective ET-1 antagonist, but do not confirm a major role for ET-1 in influencing resting forearm vascular tone in young normotensive subjects.

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