ETA receptors mediate vasoconstriction, whereas ETB receptors clear endothelin-1 in the splanchnic and renal circulation of healthy men

2003 ◽  
Vol 104 (2) ◽  
pp. 143-151 ◽  
Author(s):  
Felix BÖHM ◽  
John PERNOW ◽  
Jonas LINDSTRÖM ◽  
Gunvor AHLBORG
Keyword(s):  
Receptor Antagonist ◽  
Vascular Resistance ◽  
Vascular Tone ◽  
Renal Vasoconstriction ◽  
Healthy Humans ◽  
Arterial Blood ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist ◽  
Renal Vascular

The contribution of the endothelin (ET) receptors ETA and ETB to basal vascular tone and ET-1-induced vasoconstriction in the renal and splanchnic vasculature was investigated in six healthy humans. ET-1 was infused alone and in combination with the selective ETA receptor antagonist BQ123 or the selective ETB receptor antagonist BQ788 on three different occasions. BQ123 did not affect basal arterial blood pressure, splanchnic vascular resistance (SplVR) or renal vascular resistance (RVR), but inhibited the increase in vascular resistance induced by ET-1 [64±18 versus -1±7% in SplVR (P<0.05); 36±6 versus 12±3% in RVR (P<0.0001)]. BQ788 increased basal SplVR and RVR [38±16% (P = 0.01) and 21±5% (P<0.0001) respectively], and potentiated the ET-1-induced vasoconstriction. Plasma ET-1 increased more after ETB blockade than under control conditions or after ETA blockade. These findings suggest that the ETA receptor mediates the splanchnic and renal vasoconstriction induced by ET-1 in healthy humans. The ETB receptor seems to function as a clearance receptor and may modulate vascular tone by altering the plasma concentration of ET-1.

Endothelin stimulates an endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, in experimental heart failure

2002 ◽  
Vol 103 (s2002) ◽  
pp. 241S-244S ◽  
Author(s):  
Masato OHNISHI ◽  
Atsuyuki WADA ◽  
Takayoshi TSUTAMOTO ◽  
Masanori FUJII ◽  
Takehiro MATSUMOTO ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Vascular Resistance ◽  
Vascular Tone ◽  
Asymmetric Dimethylarginine ◽  
No Production ◽  
Plasma Adma ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
Synthase Inhibitor ◽  
Regulation Of Vascular Tone

Congestive heart failure (CHF) is characterized by increased peripheral vascular resistance. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor, is present at increased concentrations in the plasma and contributes to the regulation of vascular tone in CHF. An endothelium-derived relaxing factor, nitric oxide (NO), also regulates vascular tone, but endothelium-dependent NO-mediated vasodilation is blunted in CHF. An endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), which inhibits NO production and endothelium-dependent relaxation, is present at increased levels in the plasma and plays a role in impaired endothelial function in CHF. However, at present, the relationship between ET-1 and impaired vascular relaxation in CHF is not well known. We hypothesized that ET-1 inhibits NO-mediated vasodilation via increased ADMA production in CHF, and that an endothelin receptor antagonist can prevent this increase in plasma ADMA levels. In the present study, we first examined whether circulating ADMA levels were increased in a dog model of CHF induced by 3 weeks of rapid ventricular pacing (n = 5; 270beats/min) compared with normal dogs (n = 5). After 3 weeks of pacing, cardiac output had decreased significantly (1.56±0.16 compared with 2.93±0.25litres/min; P<0.01) and systemic vascular resistance had increased (4653±374 compared with 3227±396dyn·s·cm-5; P<0.01) in dogs with CHF compared with normal dogs. Plasma levels of both ET-1 (4.95±0.83 compared with 2.12±0.39pg/ml; P<0.05) and ADMA (3.27±0.49 compared with 1.91±0.25nmol/ml; P<0.05) were significantly increased in CHF dogs. A significant positive correlation was observed between plasma ET-1 and ADMA levels (r = 0.72, P<0.05). Secondly, we chronically administered an ETA receptor antagonist, TA-0201 (0.3mg/kg; n = 5), to paced CHF dogs. Drug administration started on day 8 of pacing and continued throughout the experiment. TA-0201 significantly increased cardiac output (2.58±0.24litres/min; P<0.01) and suppressed the increases in plasma ADMA levels and systemic vascular resistance (2.36±0.30nmol/ml and 2423±188dyn·s·cm-5 respectively; P<0.05 for each) compared with CHF dogs without TA-0201 treatment. In conclusion, ET-1 contributes to the regulation of vascular tone due, in part, to increased levels of an endogenous NO synthase inhibitor in CHF, and an ETA receptor antagonist can prevent the inhibition of NO production and the increased peripheral vascular resistance observed in CHF.

scholarly journals Muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction in healthy humans

2017 ◽  
Vol 312 (6) ◽  
pp. R956-R964 ◽  
Author(s):  
Rachel C. Drew ◽  
Cheryl A. Blaha ◽  
Michael D. Herr ◽  
Ruda Cui ◽  
Lawrence I. Sinoway
Keyword(s):  
Voluntary Contraction ◽  
Lower Limbs ◽  
Renal Vasoconstriction ◽  
Healthy Humans ◽  
Arterial Blood ◽  
Vasoconstrictor Response ◽  
Muscle Mechanoreflex ◽  
Metabolite Accumulation ◽  
Young Subjects ◽  
Renal Vascular

Reflex renal vasoconstriction occurs during exercise, and renal vasoconstriction in response to upper-limb muscle mechanoreflex activation has been documented. However, the renal vasoconstrictor response to muscle mechanoreflex activation originating from lower limbs, with and without local metabolite accumulation, has not been assessed. Eleven healthy young subjects (26 ± 1 yr; 5 men) underwent two trials involving 3-min passive calf muscle stretch (mechanoreflex) during 7.5-min lower-limb circulatory occlusion (CO). In one trial, 1.5-min 70% maximal voluntary contraction isometric calf exercise preceded CO to accumulate metabolites during CO and stretch (mechanoreflex and metaboreflex; 70% trial). A control trial involved no exercise before CO (mechanoreflex alone; 0% trial). Beat-to-beat renal blood flow velocity (RBFV; Doppler ultrasound), mean arterial blood pressure (MAP; photoplethysmographic finger cuff), and heart rate (electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as MAP/RBFV. All baseline cardiovascular variables were similar between trials. Stretch increased RVR and decreased RBFV in both trials (change from CO with stretch: RVR – 0% trial = Δ 10 ± 2%, 70% trial = Δ 7 ± 3%; RBFV – 0% trial = Δ −3.8 ± 1.1 cm/s, 70% trial = Δ −2.7 ± 1.5 cm/s; P < 0.05 for RVR and RBFV). These stretch-induced changes were of similar magnitudes in both trials, e.g., with and without local metabolite accumulation, as well as when thromboxane production was inhibited. These findings suggest that muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction, with and without muscle metaboreflex activation, in healthy humans.

scholarly journals Effects of a ETA receptor antagonist, BQ-123, on renal vasoconstriction induced by mechanical manipulation to renal artery

1995 ◽  
Vol 67 ◽  
pp. 319
Author(s):  
Yoshihiko Watarai ◽  
Mitsuhiro Yoshioka ◽  
Katsutoshi Tanda ◽  
Toshimori Seki ◽  
Hideya Saito ◽  
...  
Keyword(s):  
Renal Artery ◽  
Receptor Antagonist ◽  
Renal Vasoconstriction ◽  
Eta Receptor ◽  
Mechanical Manipulation ◽  
Eta Receptor Antagonist

Analysis of vasocontractile responses to endothelin-1 in rabbit retinal vessels using an ETA receptor antagonist and an ETB receptor agonist

Life Sciences ◽  
1993 ◽  
Vol 53 (6) ◽  
pp. PL111-PL115 ◽  
Author(s):  
Kazuo Takei ◽  
Tsuyoshi Sato ◽  
Tomohito Nonoyama ◽  
Takashi Miyauchi ◽  
Katsutoshi Goto
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Retinal Vessels ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

Decreased endothelium-dependent relaxation in subarachnoid hemorrhage-induced vasospasm: role of ET-1

1995 ◽  
Vol 269 (3) ◽  
pp. H1009-H1015 ◽  
Author(s):  
M. Zuccarello ◽  
A. Romano ◽  
M. Passalacqua ◽  
R. M. Rapoport
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Receptor Antagonist ◽  
Basilar Artery ◽  
Arterial Blood ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
Endothelium Dependent Relaxation

The purpose of this study was to test whether endothelium-dependent relaxation is decreased during acute vasospasm following subarachnoid hemorrhage (SAH) and the mechanism underlying the decrease. Basilar artery in situ was 35% constricted 3 days following injection of autologous arterial blood into the rabbit cisterna magna compared with vessels from control rabbits. In situ suffusion with the endothelium-dependent relaxant, acetylcholine (ACh; 10 microM), relaxed resting and serotonin (5-HT)-contracted control vessels but not vasospastic and 5-HT-contracted vasospastic vessels. In contrast, the relaxant potency and efficacy of ACh was similar in control and vasospastic vessels contracted with 5-HT in vitro. In situ suffusion with the ETA-receptor antagonist, BQ-123 (1 microM), reversed the vasospasm by 51% and restored the magnitude of ACh relaxation of vasospastic and 5-HT-contracted vasospastic vessels to that of controls. ACh in situ and in vitro relaxed endothelin-1 (ET-1)-contracted control vessels to a smaller magnitude than 5-HT-contracted control vessels. These results suggest, in contrast to previous studies, that endothelium-dependent relaxation is decreased during acute vasospasm following SAH. The decreased endothelium-dependent relaxation is secondary to the underlying ET-1-mediated spasm. The inhibition of endothelium-dependent relaxation observed in situ following SAH cannot be demonstrated in vitro, presumably due to loss of the ET-1-mediated vasospasm.

Differential regulation of renal regional blood flow by endothelin-1

1996 ◽  
Vol 271 (6) ◽  
pp. F1166-F1172 ◽  
Author(s):  
K. Gurbanov ◽  
I. Rubinstein ◽  
A. Hoffman ◽  
Z. Abassi ◽  
O. S. Better ◽  
...  
Keyword(s):  
Blood Flow ◽  
Receptor Antagonist ◽  
Bolus Injection ◽  
Regional Blood Flow ◽  
Doppler Flowmetry ◽  
Endothelin 1 ◽  
Male Wistar Rats ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

The present study evaluated the effects and mechanisms of action of endothelin-1 (ET-1) on medullary and cortical blood flow (MBF and CBF, respectively). CBF and MBF were measured simultaneously by laser-Doppler flowmetry in anesthetized male Wistar rats. Bolus injection of ET-1 (1.0 nmol/kg iv) produced a sustained decrease in CBF (delta = -30%) and a transient increase in MBF (delta = +35%). The medullary vasodilation induced by ET-1 was observed with doses lower than that required to produce cortical vasoconstriction; was completely blocked by bosentan, a mixed ETA/B-receptor antagonist; and was mimicked by IRL-1620, a specific ETB-receptor agonist. In contrast, BQ-123, an ETA-receptor antagonist, failed to inhibit the ET-1-dependent medullary vasodilation but effectively blocked the cortical vasoconstriction induced by the peptide. Finally, inhibition of nitric oxide (NO) synthase completely abolished, whereas cylooxygenase inhibition attenuated, the effect of ET-1 on MBF. The data demonstrate that ET-1 exerts opposite effects on renal cortical and medullary circulation, i.e., ETA-receptor-mediated cortical vasoconstriction and ETB-mediated medullary vasodilation. Furthermore, the medullary vasodilation induced by ET-1 is dependent on the NO system and, to a lesser extent, on prostaglandin generation.

Human Endothelin Subtype A Receptor Enhancement during Tissue Culture via de Novo Transcription

Neurosurgery ◽  
2002 ◽  
Vol 50 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Jacob Hansen-Schwartz ◽  
Carl-Henrik Nordström ◽  
Lars Edvinsson
Keyword(s):  
Organ Culture ◽  
Receptor Antagonist ◽  
De Novo ◽  
Cerebral Arteries ◽  
Maximal Response ◽  
Messenger Ribonucleic Acid ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

ABSTRACT OBJECTIVE Endothelin (ET) has, since its discovery, increasingly been considered a key player in the pathophysiological processes of cerebral vasospasm in the course of subarachnoid hemorrhage, although it remains unclear how ET is involved. We present data that indicate an inherent capacity of human cerebral arteries to change their sensitivity to ET. METHODS Human cerebral arteries were obtained from patients undergoing intracranial tumor surgery. The vessels were divided into segments and subjected to organ culture for 48 hours. The vessels were then examined by using in vitro pharmacological methods and molecular biological techniques. RESULTS After organ culture of the cerebral arteries, both the sensitivity to and potency of ET were enhanced (maximal response, 152 ± 9%; −log (50% effective concentration), 10.3 ± 0.3), in comparison with data for fresh cerebral arteries. Contractions were inhibited by both FR139317 (a specific ETA receptor antagonist) and bosentan (a mixed ETA and ETB receptor antagonist), in a manner indicating the sole presence of contractile ETA receptors. An inconsistent dilative response to the selective ETB receptor agonist sarafotoxin 6c was observed; the response was preserved in some segments and abolished in others, and potentiation of the precontraction was observed in yet other segments. No isolated contractile response to sarafotoxin 6c was observed, however. In reverse transcription-polymerase chain reaction assays, both ETA and ETB receptor messenger ribonucleic acid was detected. CONCLUSION These results demonstrate that human cerebral arteries are capable of enhancing the function of ETA receptors.

scholarly journals Autocrine effects of endothelin-1 on leukocyte-endothelial interaction: stimulation of endothelin B receptor subtype reduces endothelial adhesiveness via a nitric oxide-dependent mechanism

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3894-3900 ◽  
Author(s):  
T Murohara ◽  
AM Lefer
Keyword(s):  
Nitric Oxide ◽  
Receptor Antagonist ◽  
Receptor Subtype ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Endothelin B ◽  
Eta Receptor Antagonist ◽  
Inhibition Of Thrombin

The effects of endothelin-1 (ET-1) on P-selectin-mediated leukocyte endothelial interaction were examined in vitro. Adherence of autologous polymorphonuclear leukocytes (PMNs) to the endothelium was markedly enhanced by endothelial stimulation with either (2 U/mL) thrombin, (1 mumol/L) histamine, or (100 nmol/L) phorbol myristate acetate (PMA). In contrast, ET-1 alone (10 and 100 nmol/L) only slightly increased the number of adhering PMNs. The increased PMN adherence to thrombin- or histamine-stimulated endothelium, which was blocked by an anti-P-selectin monoclonal antibody, was also significantly attenuated by preincubation of coronary segments with (100 nmol/L) ET-1. We further investigated the mechanism of this anti-adherence action of ET-1 on thrombin-stimulated endothelial adhesiveness. Preincubation of coronary segments with a selective ETA receptor antagonist, BQ485 (1 mumol/L), had no effect on ET-1 inhibition of thrombin-induced PMN adherence. In contrast, preincubation with a selective ETB receptor antagonist, BQ788 (1 mumol/L) significantly reversed ET-1 inhibition of thrombin-induced PMN adherence, whereas the selective ETB receptor agonist BQ-3020 mimicked the inhibitory action of ET-1 on thrombin-induced PMN adherence. Furthermore, (100 mumol/L) N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, significantly attenuated ET-1 inhibition of thrombin-stimulated PMN adherence. These results suggest that ET-1 may inhibit P-selectin-mediated leukocyte-endothelial interaction via ETB receptor stimulation and subsequent endothelial NO formation. This autocrine effect of ET-1 may be involved in pathophysiologic states such as early atherogenesis by preventing leukocyte-endothelial interaction in constricted blood vessels.

Myogenic contribution to agonist-induced renal vasoconstriction during normoxia and hypoxia

1997 ◽  
Vol 272 (4) ◽  
pp. H1945-H1951 ◽  
Author(s):  
M. R. Eichinger ◽  
J. M. Resta ◽  
B. R. Walker
Keyword(s):  
Renal Artery ◽  
Vascular Resistance ◽  
Acute Hypoxia ◽  
Renal Perfusion ◽  
Renal Vascular Resistance ◽  
Left Renal Artery ◽  
Sprague Dawley ◽  
Renal Vasoconstriction ◽  
Arterial Blood ◽  
Renal Vascular

Acute hypoxia attenuates agonist-induced constrictor and pressor responses in conscious rats, and a recent report suggests that hypoxia may also diminish myogenic reactivity in isolated, perfused rat kidneys. Thus we hypothesized that the diminished responsiveness to pressor agents during hypoxia is caused by an impairment of myogenic reactivity. Male Sprague-Dawley rats were instrumented with a pulsed Doppler flow probe on the left renal artery, an aortic vascular occluder cuff immediately above the left renal artery to control renal perfusion pressure, and catheters were inserted to measure systemic arterial blood pressure and renal arterial pressure (RAP) and for administration of agents. Animals were studied under normoxic or acute hypoxic (fractional concentration of O2 in inspired gials = 0.12) conditions and were administered phenylephrine, arginine vasopressin, or angiotensin II. To determine the myogenic (pressure-dependent) component of agonist-induced vasoconstriction, renal vascular resistance was calculated during agonist infusion with RAP uncontrolled and with RAP controlled to preinfusion levels. Significant myogenic components of agonist-induced renal vasoconstriction were evident with all pressor agents used. However, hypoxia did not attenuate agonist-induced, pressure-dependent increases in renal vascular resistance. We conclude that the reduced vasoreactivity associated with acute hypoxia is not caused by diminished myogenic reactivity.

Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle

1997 ◽  
Vol 273 (1) ◽  
pp. H119-H127 ◽  
Author(s):  
Y. Zhu ◽  
H. T. Yang ◽  
M. Endoh
Keyword(s):  
Receptor Antagonist ◽  
Positive Inotropic Effect ◽  
Dominant Role ◽  
Negative Inotropic Effect ◽  
Camp Level ◽  
Inotropic Effect ◽  
Inotropic Effects ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

In isolated rabbit right atria, endothelin (ET) isopeptides ET-1 and ET-3 elicited a concentration-dependent negative chronotropic effect (NCE) in the presence of isoproterenol (Iso): ET-1 was approximately 10 times more potent than ET-3. The NCE of ET-1 was abolished by the ETA- and ETB-receptor antagonist TAK-044 (1 microM) or the ETA-receptor antagonist BQ-123 (10 microM), but it was not affected by the ETB-receptor antagonist RES-701-1 or BQ-788. ET-1 decreased the adenosine 3',5'-cyclic monophosphate (cAMP) level in the presence of Iso in rabbit atria. Pretreatment with pertussis toxin (PTX) markedly attenuated the NCE of ET-1 and abolished the decrease in the cAMP level induced by ET-1. In isolated dog ventricular trabeculae, ET-1 elicited a pronounced negative inotropic effect (NIE), whereas ET-3 induced a small but significant positive inotropic effect in the presence of Iso. The NIE was abolished by the ETA-receptor antagonist BQ-123 (1 microM) and partially attenuated by the ETB-receptor antagonist RES-701-1. The positive inotropic effect of ET-3 was abolished by RES-701-1. Although pretreatment with PTX markedly attenuated the NIE of ET-1, cAMP levels in dog ventricular muscle were not decreased by ET-1. These results indicate that activation of an ETA receptor that is coupled to the PTX-sensitive G protein plays a dominant role in the NCE and NIE of ET-1. The NCE of ET-1 may, in part, be due to a decrease in cAMP level. By contrast, the NIE of ET-1 does not involve an alteration of cAMP accumulation. The present findings imply that ET isopeptides might antagonize the cardiostimulatory action of catecholamines mediated by beta-adrenoceptors when the blood level of both endogenous regulators are increased under cardiovascular pathophysiological situations.

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