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.

Ex Vivo Inhibition of Platelet Aggregation in Patients with Severe Limb Arteriopathy Treated with BAY U3405, a Specific IX A2 Receptor Antagonist

1994 ◽  
Vol 72 (05) ◽  
pp. 659-662 ◽  
Author(s):  
S Bellucci ◽  
W Kedra ◽  
H Groussin ◽  
N Jaillet ◽  
P Molho-Sabatier ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Randomized Study ◽  
In Vivo Studies ◽  
Walking Distance ◽  
Peripheral Blood Flow ◽  
Walking Ability ◽  
Double Blind ◽  
Platelet Factor

SummaryA double-blind, placebo-controlled randomized study with BAY U3405, a specific thromboxane A2 (TX A2) receptor blocker, was performed in patients suffering from severe stade II limb arteriopathy. BAY U3405 or placebo was administered in 16 patients at 20 mg four times a day (from day 1 to day 3). Hemostatic studies were done before therapy, and on day 2 and day 3 under therapy. On day 3, BAY U3405 was shown to induce a highly statistically significant decrease of the velocity and the intensity of the aggregations mediated by arachidonic acid (56 ± 37% for the velocity, 58 ± 26% for the intensity) or by U46619 endoperoxide analogue (36 ± 35% for the velocity, 37 ± 27% for the intensity). Similar results were already observed on day 2. By contrast, such a decrease was not noticed with ADP mediated platelet aggregation. Furthermore, plasma levels of betathrombo-globulin and platelet factor 4 remained unchanged. Peripheral hemodynamic parameters were also studied. The peripheral blood flow was measured using a Doppler ultrasound; the pain free walking distance and the total walking ability distance were determined under standardized conditions on a treadmill. These last two parameters show a trend to improvement which nevertheless was not statistically significant. All together these results encourage further in vivo studies using BAY U3405 or related compounds on a long-term administration.

Failure of prostaglandins to modulate the time course of blood flow during dynamic forearm exercise in humans

1996 ◽  
Vol 81 (4) ◽  
pp. 1516-1521 ◽  
Author(s):  
J. K. Shoemaker ◽  
H. L. Naylor ◽  
Z. I. Pozeg ◽  
R. L. Hughson
Keyword(s):  
Blood Flow ◽  
Brachial Artery ◽  
Time Course ◽  
Forearm Blood Flow ◽  
Voluntary Contraction ◽  
Double Blind ◽  
Rate Of Increase ◽  
Forearm Exercise ◽  
Blind Manner ◽  
Exercise In Humans

Shoemaker, J. K., H. L. Naylor, Z. I. Pozeg, and R. L. Hughson. Failure of prostaglandins to modulate the time course of blood flow during dynamic forearm exercise in humans. J. Appl. Physiol. 81(4): 1516–1521, 1996.—The time course and magnitude of increases in brachial artery mean blood velocity (MBV; pulsed Doppler), diameter ( D; echo Doppler), mean perfusion pressure (MPP; Finapres), shear rate (γ˙ = 8 ⋅ MBV/ D), and forearm blood flow (FBF = MBV ⋅ π r 2) were assessed to investigate the effect that prostaglandins (PGs) have on the hyperemic response on going from rest to rhythmic exercise in humans. While supine, eight healthy men performed 5 min of dynamic handgrip exercise by alternately raising and lowering a 4.4-kg weight (∼10% maximal voluntary contraction) with a work-to-rest cycle of 1:1 (s/s). When the exercise was performed with the arm positioned below the heart, the rate of increase in MBV and γ˙ was faster compared with the same exercise performed above the heart. Ibuprofen (Ibu; 1,200 mg/day, to reduce PG-induced vasodilation) and placebo were administered orally for 2 days before two separate testing sessions in a double-blind manner. Resting heart rate was reduced in Ibu (52 ± 3 beats/min) compared with placebo (57 ± 3 beats/min) ( P < 0.05) without change to MPP. With placebo, D increased in both arm positions from ∼4.3 mm at rest to ∼4.5 mm at 5 min of exercise ( P < 0.05). This response was not altered with Ibu ( P > 0.05). Ibu did not alter the time course of MBV or forearm blood flow ( P > 0.05) in either arm position. The γ˙ was significantly greater in Ibu vs. placebo at 30 and 40 s of above the heart exercise and for all time points after 25 s of below the heart exercise ( P < 0.05). Because PG inhibition altered the time course ofγ˙ at the brachial artery, but not FBF, it was concluded that PGs are not essential in regulating the blood flow responses to dynamic exercise in humans.

Dilator actions of arginine in human peripheral vasculature

1991 ◽  
Vol 81 (5) ◽  
pp. 695-700 ◽  
Author(s):  
Alison Calver ◽  
Joe Collier ◽  
Patrick Vallance
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Forearm Blood Flow ◽  
Hypotensive Effect ◽  
Linear Displacement ◽  
High Dose ◽  
Free Base ◽  
Peripheral Vasculature ◽  
Arginine Hydrochloride

1. l-Arginine is the physiological precursor for the formation of endothelium-derived nitric oxide. The synthesis of nitric oxide is stereospecific: d-arginine is not a substrate for nitric oxide synthase. It is possible that the provision of excess l-arginine substrate might increase the vascular synthesis of nitric oxide. We have examined this possibility by studying the effects of local infusion of l-and d-arginine in the forearm resistance bed and the superficial dorsal hand veins of healthy subjects. 2. Drugs were either infused locally into a vein on the back of the hand and then the vein diameter was measured using a linear displacement technique, or into the brachial artery and then the forearm blood flow was measured by venous occlusion plethysmography. 3. In the superficial hand veins, l- and d-arginine free base and l- and d-arginine hydrochloride (all four preparations at a dose of 5 μmol/min) all caused a significant increase in venous diameter. The responses of the l-and d-enantiomers did not differ significantly from one another. 4. In the forearm resistance bed, l- and d-arginine free base and l-arginine hydrochloride were without effect at doses of 10 and 40 μmol/min. However, at doses of 160 μmol/min all three preparations of arginine caused a significant increase in forearm blood flow compared with control values. The responses to the three preparations of arginine did not differ significantly from one another. 5. These results show that arginine in high dose is a vasodilator in both human resistance vessels and superficial veins in vivo. The response to arginine was not stereospecific: both the l- and d-enantiomers had the same effect. The dilator effect of high-dose arginine showed neither arterio-nor veno-selectivity. 6. This suggests that the hypotensive effect of systemic infusions of l-arginine in man is mediated by peripheral vasodilatation. It is not possible to ascribe the actions of arginine supplementation in this study to activation of the l-arginine/nitric oxide pathway through the provision of excess substrate.

Abstract 3628: Neuronal Nitric Oxide Synthase (nNOS) Regulates Basal Flow in the Human Coronary Circulation I n Vivo

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Mike Seddon ◽  
Phil Chowienczyk ◽  
Narbeh Melikian ◽  
Rafal Dworakowski ◽  
Barbara Casadei ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Substance P ◽  
Coronary Flow ◽  
Vascular Tone ◽  
Coronary Circulation ◽  
Physiological Regulation ◽  
Intracoronary Doppler ◽  
Basal Flow

Endothelial NO synthase (eNOS) is thought to be the major source of nitric oxide (NO) involved in the local regulation of human vascular tone. However, in studies using a selective neuronal NOS (nNOS) inhibitor S-methyl-L-thiocitrulline (SMTC), we recently reported that basal human forearm blood flow is regulated by nNOS. SMTC had no effect on acetylcholine-induced vasodilatation which however was inhibited by the non-selective NOS inhibitor N G monomethyl-L-arginine (L-NMMA). This study investigated the effects of nNOS in the human coronary circulation in vivo . We studied patients undergoing diagnostic cardiac catheterisation who had angiographically normal coronary arteries. Coronary flow velocity was measured by an intracoronary Doppler wire and epicardial artery diameter by QCA. We compared the effects of intracoronary SMTC or L-NMMA infusion on basal flow and the responses to substance P and isosorbide dinitrate (endothelium-dependent and -independent dilators, respectively). L-NMMA (25 μmol/min) reduced basal coronary flow by 22.3±5.3% and inhibited dilation to substance P (20 pmol/min) by 57±5.7% (n=8; both P<0.01). SMTC (0.625 μmol/min) also reduced basal flow (−34.8±6.3%; n=8; P<0.01), but had no effect on the response to substance P (inhibited by −2±14%; P=NS). The effects of SMTC were abolished by L-arginine (240μmol/ min; n=3). Both L-NMMA and SMTC reduced epicardial artery diameter (−2.5±0.6% and −2.8±0.9% respectively; P<0.05) but only L-NMMA reduced dilatation to substance P (5.6±1.3% before versus 3.0±0.8% after L-NMMA; P<0.05). These data indicate that local nNOS-derived NO regulates basal coronary blood flow in humans in vivo , whereas substance P-stimulated vasodilatation is eNOS-mediated. Our results indicate that nNOS and eNOS have distinct local roles in the physiological regulation of human coronary vascular tone in vivo .

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.

Direct effect of α-human atrial natriuretic peptide on human vasculature in vivo and in vitro

1988 ◽  
Vol 74 (2) ◽  
pp. 207-211 ◽  
Author(s):  
A. Hughes ◽  
S. Thom ◽  
P. Goldberg ◽  
G. Martin ◽  
P. Sever
Keyword(s):  
Blood Flow ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Forearm Blood Flow ◽  
Renin Angiotensin System ◽  
Organ Bath ◽  
Human Atrial Natriuretic Peptide ◽  
Atrial Natriuretic

1. The effect of a α-human atrial natriuretic peptide (1–28) (ANP) on human vasculature was investigated in vivo and in vitro. Possible involvement of vascular dopamine receptors and the renin-angiotensin system in the response to ANP was also studied in vivo. 2. Forearm blood blow was measured by venous occlusion plethysmography. Isolated human blood vessels were studied using conventional organ bath techniques. 3. ANP (0.1–1 μg/min, intra-arterially) produced a dose-dependent increase in forearm blood flow, corresponding to a 163% increase in net forearm blood flow in the study arm. This action of ANP was not antagonized by (R)-sulpiride (100 μg/min, intra-arterially), a selective vascular dopamine receptor antagonist, or 50 mg of oral captopril, an inhibitor of angiotensin-converting enzyme. 4. ANP (1 nmol/l–1 μmol/l) produced concentration-dependent relaxation of isolated human arteries, including brachial artery, but was without effect on isolated human saphenous vein. 5. ANP produces vasodilatation in vivo and relaxes isolated human arterial smooth muscle. This action of ANP may contribute to its reported hypotensive effects in vivo.

Comparison of two indices for forearm noradrenaline release in humans

2000 ◽  
Vol 99 (5) ◽  
pp. 363-369 ◽  
Author(s):  
Gerard A. RONGEN ◽  
Jacques W. M. LENDERS ◽  
Paul SMITS ◽  
John S. FLORAS
Keyword(s):  
Blood Flow ◽  
Sodium Nitroprusside ◽  
Noradrenaline Release ◽  
Negative Pressure ◽  
Forearm Blood Flow ◽  
Lower Body Negative Pressure ◽  
Lower Body ◽  
Release Of Noradrenaline ◽  
Appearance Rate

Although there is as yet no method which measures directly the neuronal release of noradrenaline in humans in vivo, the isotope dilution technique with [3H]noradrenaline has been applied to estimate forearm neuronal noradrenaline release into plasma. Two different equations have been developed for this purpose: one to estimate the spillover of noradrenaline into the venous effluent, and a modified formula (often referred to as the appearance rate) which may reflect more closely changes in the neuronal release of noradrenaline into the synaptic cleft, particularly during interventions that alter forearm blood flow. The present study was performed to compare the effects of two interventions known to exert contrasting actions on neuronal forearm noradrenaline release and forearm blood flow. Intra-arterial infusion of sodium nitroprusside at doses without systemic effect increases forearm blood flow, but not neuronal noradrenaline release. In contrast, lower-body negative pressure at -25 mmHg causes forearm vasoconstriction by stimulating neuronal noradrenaline release. During sodium nitroprusside infusion, forearm noradrenaline spillover increased from 1.1±0.3 to 2.2±1.0 pmol·min-1·100 ml-1 (P < 0.05), whereas the forearm noradrenaline appearance rate was unchanged. Lower-body negative pressure did not affect the forearm noradrenaline spillover rate, but increased the forearm noradrenaline appearance rate from 3.4±0.4 pmol·min-1·100 ml-1 at baseline to 5.0±0.9 pmol·min-1·100 ml-1 (P < 0.05). These results indicate that the noradrenaline appearance rate provides the better approximation of changes in forearm neuronal noradrenaline release in response to stimuli which alter local blood flow.

scholarly journals Pseudocontinuous Arterial Spin Labeling Reveals Dissociable Effects of Morphine and Alcohol on Regional Cerebral Blood Flow

2011 ◽  
Vol 31 (5) ◽  
pp. 1321-1333 ◽  
Author(s):  
Najmeh Khalili-Mahani ◽  
Matthias JP van Osch ◽  
Evelinda Baerends ◽  
Roelof P Soeter ◽  
Marieke de Kam ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Repeated Measures ◽  
Arterial Spin Labeling ◽  
Randomized Study ◽  
Spin Labeling ◽  
Statistical Testing ◽  
Anterior Cingulate ◽  
Double Blind ◽  
Mixed Effect

We have examined sensitivity and specificity of pseudocontinuous arterial spin labeling (PCASL) to detect global and regional changes in cerebral blood flow (CBF) in response to two different psychoactive drugs. We tested alcohol and morphine in a placebo-controlled, double-blind randomized study in 12 healthy young men. Drugs were administered intravenously. Validated pharmacokinetic protocols achieved minimal intersubject and intrasubject variance in plasma drug concentration. Permutation-based statistical testing of a mixed effect repeated measures model revealed a widespread increase in absolute CBF because of both morphine and alcohol. Conjunction analysis revealed overlapping effects of morphine and alcohol on absolute CBF in the left anterior cingulate, right hippocampus, right insula, and left primary sensorimotor areas. Effects of morphine and alcohol on relative CBF (obtained from z-normalization of absolute CBF maps) were significantly different in the left putamen, left frontoparietal network, cerebellum, and the brainstem. Corroborating previous PET results, our findings suggest that PCASL is a promising tool for central nervous system drug research.

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.

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