Evidence for the existence of endothelin-B receptor subtypes and their physiological roles in the rat

1996 ◽  
Vol 271 (1) ◽  
pp. R254-R261 ◽  
Author(s):  
M. Gellai ◽  
T. Fletcher ◽  
M. Pullen ◽  
P. Nambi
Keyword(s):  
Radioligand Binding ◽  
Rat Kidney ◽  
Receptor Subtypes ◽  
Sprague Dawley ◽  
Vascular Effects ◽  
Renal Vasoconstriction ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Endothelin B

The physiological roles of endothelin-B (ETB) receptor subtypes in systemic and renal hemodynamics were assessed in conscious Sprague-Dawley rats. Mean arterial pressure, hindlimb flow, and renal blood flow were measured via an implanted catheter and pulsed Doppler flow probes. Bolus intravenous injections of sarafotoxin 6c (S6c), a selective ETB agonist, elicited transient dose-dependent vasodilation, followed by sustained vasoconstriction in the systemic bed, but only vasoconstriction in the renal bed. RES-701-1, a selective ETB antagonist, blocked the dilator and potentiated the constrictor effect; SB-209670, a mixed ET receptor antagonist, attenuated both responses to S6c. In follow-up studies, the role of endogenous ET was assessed by administration of the antagonists alone: RES-701-1, SB-209670, and the ETA-selective antagonist BQ-123. RES-701-1 unmasked a significant systemic and renal vasoconstriction, which was attenuated by SB-209670 but not by BQ-123. SB-209670 and BQ-123 had no effect on basal hemodynamic parameters. Data from radioligand binding experiments showed that RES-701-1 binds with high affinity to the cloned human ETB receptor but poorly to the ETB receptor predominant in the rat kidney. Collectively, the results indicate that 1) the vascular effects of ET in the rat are mediated by two ETB receptor subtypes: an RES-701-1-sensitive subtype, mediating vasodilation, and an RES-701-1-insensitive subtype, mediating vasoconstriction; 2) the predominant role of endogenous ET is vasodilation; and 3) the ETA receptor plays a negligible role in the control of vascular tone in the rat.

Role of endothelin receptor subtypes in the in vivo regulation of renal function

1995 ◽  
Vol 268 (3) ◽  
pp. F455-F460 ◽  
Author(s):  
A. L. Clavell ◽  
A. J. Stingo ◽  
K. B. Margulies ◽  
R. R. Brandt ◽  
J. C. Burnett
Keyword(s):  
Sodium Excretion ◽  
Urine Osmolality ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Low Doses ◽  
Renal Vasoconstriction ◽  
Etb Receptor ◽  
Diuretic Response

Endothelin (ET) is a potent vasoconstrictor peptide of endothelial origin, which at low doses results in renal vasoconstriction and diuresis with variable actions on sodium excretion. The current study conducted in four groups of anesthetized dogs was designed to define the role of the ETA and ETB receptor subtypes in the renal actions of low-dose exogenous ET. Group 1 (n = 4) animals served as time controls. In group 2 (n = 6) a systemic ET-1 (5 ng.kg-1.min-1) infusion mediated renal vasoconstriction, antinatriuresis with increases in proximal fractional reabsorption of sodium, and diuresis with a decrease in urine osmolality. In group 3 (n = 6) intrarenal BQ-123 (4 micrograms.kg-1.min-1), a selective ETA antagonist, abolished the systemic ET-1-mediated changes in renal hemodynamics and unmasked a natriuretic action at the level of the proximal tubule. In contrast, the diuretic response of ET was not altered by BQ-123. In group 4 (n = 6) intrarenal sarafotoxin 6-c, a selective ETB receptor agonist, resulted in a diuretic response without a change in sodium excretion. These studies suggest that the ETA receptor contributes to the renal vasoconstriction, whereas the ETB receptor is largely responsible for the diuretic response during exogenous ET. This study also suggests that at low doses ET is natriuretic in vivo by decreasing proximal tubular reabsorption of sodium independent of ETA or ETB receptor activation.

Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention

2006 ◽  
Vol 291 (6) ◽  
pp. F1274-F1280 ◽  
Author(s):  
Yuqiang Ge ◽  
Alan Bagnall ◽  
Peter K. Stricklett ◽  
Kevin Strait ◽  
David J. Webb ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Receptor Gene ◽  
Plasma Renin ◽  
High Salt ◽  
Paracrine Effects ◽  
High Sodium ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Endothelin B

Collecting duct (CD)-derived endothelin-1 (ET-1) inhibits renal Na reabsorption and its deficiency increases blood pressure (BP). The role of CD endothelin B (ETB) receptors in mediating these effects is unknown. CD-specific knockout of the ETB receptor was achieved using an aquaporin-2 promoter-Cre recombinase transgene and the loxP-flanked ETB receptor gene (CD ETB KO). Systolic BP in mice with CD-specific knockout of the ETB receptor, ETA receptor (CD ETA KO) and ET-1 (CD ET-1 KO), and their respective controls were compared during normal- and high-salt diet. On a normal-sodium diet, CD ETB KO mice had elevated BP, which increased further during high salt feeding. However, the degree of hypertension in CD ETB KO mice and the further increase in BP during salt feeding were lower than that of CD ET-1 KO mice, whereas CD ETA KO mice were normotensive. CD ETB KO mice had impaired sodium excretion following acute sodium loading. Aldosterone and plasma renin activity were decreased in CD ETB KO mice on normal- and high-sodium diets, while plasma and urinary ET-1 levels did not differ from controls. In conclusion, the CD ETB receptor partially mediates the antihypertensive and natriuretic effects of ET-1. CD ETA and ETB receptors do not fully account for the antihypertensive and natriuretic effects of CD-derived ET-1, suggesting paracrine effects of this peptide.

Abstract 244: Increased Expression and Enhanced Vasorelaxation Activity of Specific Estrogen Receptor Subtypes in the Aorta and Mesenteric Vessels during Pregnancy

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Karina M Mata ◽  
Wei Li ◽  
Ossama M Reslan ◽  
Waleed T Siddiqui ◽  
Lauren A Opsasnick ◽  
...  
Keyword(s):  
Renal Artery ◽  
Mesenteric Artery ◽  
Receptor Subtypes ◽  
Vascular Effects ◽  
Western Blots ◽  
Expression Activity ◽  
Mesenteric Vessels ◽  
Nos Inhibitor ◽  
Dependent Mechanism

Pregnancy (Preg) is associated with hormonal and vascular changes, and estrogen (E2) may promote systemic vasodilation during Preg; however, the specific E2 receptor (ER), post-ER signaling mechanisms and vascular bed involved are unclear. To test if Preg is associated with distinct expression/activity of ERs in different blood vessels, BP and plasma E2 were measured in virgin and day-19 Preg rats, and the aorta, carotid, mesenteric and renal artery were isolated for measurement of ERα, ERβ and GPR30 expression, and the responses to E2 and specific ER agonists PPT (ERα), DPN (ERβ) and G1 (GPR30). BP was in Preg (89±6) < virgin (98±4mmHg), and plasma E2 was in Preg (120.5±5.8) > virgin (94.3±7.5pg/ml). Western blots revealed increased ERα and ERβ in aorta and mesenteric artery and GPR30 in aorta of Preg vs virgin. Immunohistochemistry revealed that the increases in ERs were mainly in intima and media. E2 and PPT caused greater relaxation of aorta of Preg (52.8±5.5, 49.3±11.4) than virgin (30.0±3.9, 19.3±3.8%) and of mesenteric artery of Preg (77.9±4.7, 75.4±4.5) than virgin (57.4±5.9, 46.5±9.5%), but similar relaxation in carotid and renal artery of Preg vs virgin. DPN and G1 caused greater relaxation in mesenteric and renal artery (15 to 30%) than aorta and carotid artery (<10%), but only aortic relaxation to G1 was in Preg (26.2±4.4) > virgin (5.3±6.7%). The NOS inhibitor L-NAME ± EDHF blocker tetraethylammonium or endothelium removal reduced PPT relaxation in aorta, suggesting an endothelium-dependent mechanism, but did not affect E2, PPT, DPN or G1-induced relaxation in other vessels, suggesting endothelium-independent mechanisms. PPT caused relaxation of Ca 2+ entry-dependent KCl contraction of mesenteric artery that was in Preg (69.7±5.5) > virgin rats (52.9±8.11%). Thus, during pregnancy, an increased ERα expression in endothelial and smooth muscle layers of aorta and mesenteric artery is associated with increased ERα-mediated relaxation via endothelium-derived vasodilators and direct inhibition of Ca 2+ entry pathways, supporting a role of aortic and mesenteric arterial ERα in pregnancy-associated systemic vasodilation. GPR30 may contribute to aortic dilation while the enhanced ERβ may mediate other genomic vascular effects during pregnancy.

scholarly journals Contrasting pharmacological ETB receptor blockade with genetic ETB deficiency in renal responses to big ET-1

2001 ◽  
Vol 6 (1) ◽  
pp. 39-43 ◽  
Author(s):  
DAVID M. POLLOCK
Keyword(s):  
Renal Plasma Flow ◽  
Urine Flow ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Clearance Studies ◽  
Etb Receptor ◽  
Pharmacological Blockade ◽  
Series Of Experiments ◽  
Renal Responses

Renal clearance studies were conducted to determine the role of ETB receptors in the renal response to big endothelin-1 (big ET-1). Two series of experiments were conducted on Inactin-anesthetized rats to contrast acute pharmacological blockade of ETB receptors vs. genetic ETB receptor deficiency. In the first series, Sprague-Dawley rats were given either ETB-selective antagonist, A-192621, or vehicle (0.9% NaCl) prior to infusion of big ET-1 (10 pmol·kg−1·min−1) for 60 min. A-192621 significantly increased baseline mean arterial pressure (MAP; 102 ± 4 vs. 141 ± 6 mmHg, P < 0.05) and urine flow rate (0.5 ± 0.1 vs. 1.3 ± 0.2 μl/min, P < 0.05) without any effect on glomerular filtration rate (GFR) or effective renal plasma flow (ERPF). Big ET-1 significantly increased MAP in both groups but to a higher level in rats given antagonist (120 ± 6 vs. 169 ± 6 mmHg, P < 0.05). Big ET-1 increased urine flow in control rats but decreased in rats given antagonist. GFR and ERPF were decreased in rats given big ET-1, an effect that was exaggerated by ETB blockade. Another series of experiments examined the response to big ET-1 in rats lacking functional renal ETB receptors, known as spotting lethal ( sl) rats. Surprisingly, rats heterozygous ( sl/+) for ETB receptor deficiency had a significantly higher baseline MAP compared with homozygous ( sl/ sl) rats (134 ± 6 vs. 112 ± 7 mmHg, P < 0.05), although other variables were similar. Big ET-1 produced no significant change in MAP in either group. Urine flow, GFR, and ERPF were significantly decreased in both groups, although these changes were much larger in sl/ sl rats. These experiments indicate that the ETB receptor plays an important role in limiting the renal hemodynamic response to big ET-1. Furthermore, the diuretic actions of big ET-1 require a functional ETB receptor.

Acute cyclosporine-induced renal vasoconstriction: lack of effect of theophylline

1990 ◽  
Vol 258 (1) ◽  
pp. F41-F45
Author(s):  
P. C. Churchill ◽  
N. F. Rossi ◽  
M. C. Churchill ◽  
A. K. Bidani ◽  
F. D. McDonald
Keyword(s):  
Renal Plasma Flow ◽  
Left Kidney ◽  
Chronic Administration ◽  
Sprague Dawley ◽  
Renal Vasoconstriction ◽  
Adenosine Receptor Antagonist ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Group 1

Both acute and chronic administration of cyclosporine A (CSA) lead to renal vasoconstriction, but the mechanism is not fully understood. The present studies were designed to explore the possible role of adenosine in acute CSA-induced renal vasoconstriction in rats. Six groups of anesthetized Sprague-Dawley rats were studied using standard clearance techniques: group 1 rats were controls; groups 2, 4, and 6 received CSA intravenously at 20, 30, and 40 mg.h-1.kg body wt-1, respectively; groups 3 and 5 were identical to groups 2 and 4 except that a priming injection of theophylline was given (56 mumol/kg body wt) and theophylline was included in the intravenous infusate (0.56 mumol.min-1.kg body wt-1). CSA produced acute and concentration-dependent reductions in renal plasma flow (left kidney) and in the clearances of p-aminohippuric acid and inulin (both kidneys). Except in group 6, these changes were observed in the absence of a decrease in arterial blood pressure, demonstrating that CSA produced an acute and concentration-dependent increase in renovascular resistance. Theophylline not only failed to block CSA-induced renal vasoconstriction, if anything, it potentiated it. Because theophylline is an adenosine receptor antagonist, these findings contradict the hypothesis that adenosine mediates acute CSA-induced renal vasoconstriction.

Pulmonary vascular pressure effects by endothelin-1 in normoxia and chronic hypoxia: a longitudinal study

1996 ◽  
Vol 271 (6) ◽  
pp. H2246-H2253 ◽  
Author(s):  
S. Tjen-A-Looi ◽  
R. Ekman ◽  
J. Osborn ◽  
I. Keith
Keyword(s):  
Pulmonary Hypertension ◽  
Ventricular Hypertrophy ◽  
Pressure Effects ◽  
Blood Levels ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Calcitonin Gene ◽  
Eta Receptor ◽  
Pulmonary Arterial

The role of endothelin (ET)-1 in pulmonary arterial pressure (Ppa) homeostasis and hypoxia-induced pulmonary hypertension was examined. ET-1 was chronically infused (2 and 4 pmol.kg-1.min-1) into the pulmonary circulation of male Sprague-Dawley rats for 3, 7, and 14 days while they were exposed to normoxia or hypobaric hypoxia (inspired O2 fraction 10%). The role of endogenous ET was examined by infusion of ET antiserum (ET-AS; 0.25 and 0.5 microliter.rat-1.h-1; cross-reacting with ET-1, -2, and -3) or the ETA-receptor blocker BQ-123 (10 pmol.kg-1.min-1). ET-1 (4 pmol) increased Ppa at 3 and 7 days in normoxia and hypoxia and was ineffective at 14 days, probably from ETA-receptor downregulation. BQ-123 blunted the hypoxic Ppa rise at all times, confirming a role for ETA receptors. ET-AS (0.5 microliter) was mostly ineffective but exacerbated hypoxic Ppa at 14 days, in contrast to BQ-123, suggesting that a different ET receptor could be involved. ET-1 infusion (2 pmol) caused right ventricular hypertrophy (RVH) in normoxia and exacerbated RVH in hypoxia, whereas BQ-123 and ET-AS (0.25 microliter) reduced hypoxic RVH. In conclusion, endogenous ET-1 plays a role in hypoxia-induced pulmonary hypertension and RVH by augmenting the level of hypoxic response. ET-1 also affects hematocrit and may reduce blood levels of the vasodilator calcitonin gene-related peptide.

Mechanism of prostaglandin E2-induced increase of proximal sodium reabsorption in the rat

1990 ◽  
Vol 258 (1) ◽  
pp. R82-R86 ◽  
Author(s):  
Y. Kinoshita ◽  
F. G. Knox
Keyword(s):  
Angiotensin Ii ◽  
Prostaglandin E2 ◽  
Rat Kidney ◽  
Sodium Reabsorption ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Convoluted Tubules ◽  
Stimulation Of ◽  
Interstitial Infusion

Prostaglandin E2, when infused directly into the renal interstitium, enhances sodium reabsorption by the superficial proximal convoluted tubules of anesthetized Sprague-Dawley rats. The present study was designed to investigate the role of angiotensin II in the prostaglandin E2-induced stimulation of proximal sodium reabsorption. Micropuncture at the superficial late proximal tubule demonstrated a significant increase in the fractional reabsorption of sodium from 39.9 +/- 2.3% in control conditions to 51.8 +/- 3.0% (n = 9, P less than 0.01) during the renal interstitial infusion of prostaglandin E2. The stimulatory effect of prostaglandin E2 on proximal sodium reabsorption was markedly attenuated by pretreatment with saralasin. During intravenous saralasin infusion, prostaglandin E2 did not significantly change the fractional reabsorption of sodium from 42.2 +/- 5.8 to 45.4 +/- 6.0% (n = 7, NS). In summary, the stimulatory effect of renal interstitial infusion of prostaglandin E2 on proximal sodium reabsorption was attenuated by pretreatment with saralasin. Therefore renal interstitial infusion of prostaglandin E2 may enhance proximal sodium reabsorption, at least in part, through stimulation of angiotensin II production in the rat kidney.

Renal effects of prolonged high protein intake and COX2 inhibition on hypertensive rats with altered renal development

2011 ◽  
Vol 301 (2) ◽  
pp. F327-F333 ◽  
Author(s):  
Virginia Reverte ◽  
Antonio Tapia ◽  
Juan Manuel Moreno ◽  
Leocadio Rodríguez ◽  
Francisco Salazar ◽  
...  
Keyword(s):  
Renal Function ◽  
Protein Intake ◽  
High Protein ◽  
Renal Development ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
High Protein Intake ◽  
Renal Vasoconstriction ◽  
Renal Ablation

Cyclooxygenase 2 (COX2) is involved in regulating renal hemodynamics after renal ablation. It is also known that high protein intake (HPI) leads to a deterioration of renal function when there is preexisting renal disease and that there are important gender differences in the regulation of renal function. This study tested the hypothesis that the role of COX2 in regulating renal function and the renal hemodynamic effects elicited by HPI are enhanced when nephrogenesis is altered during renal development. It was also expected that the role of COX2 and the effects elicited by HPI are age and sex dependent. Newborn Sprague-Dawley rats were treated with an AT1 ANG II receptor antagonist during the nephrogenic period (ARAnp). Experiments were performed at 3–4 and 10–11 mo of age. Arterial pressure was elevated ( P < 0.05) at both ages and in both sexes of ARAnp-treated rats. Renal COX2 expression was only elevated ( P < 0.05) at 10–11 mo of age in both sexes of ARAnp-treated rats. COX2 inhibition induced greater renal vasoconstriction in male and female hypertensive than in normotensive rats at both ages. HPI did not induce glomerular filtration rate (GFR) in the youngest hypertensive rats and in the oldest female hypertensive rats. However, the GFR decreased during HPI (0.63 ± 0.07 to 0.19 ± 0.05 ml/min) in the oldest male hypertensive rats. The HPI-induced increment in proteinuria was greater ( P < 0.05) in male (99 ± 22 mg/day) than in female (30 ± 8 mg/day) hypertensive rats. These results show that COX2 plays an important role in the regulation of renal function when renal development is altered and that prolonged HPI can lead to a renal insufficiency in males but not in females with reduced nephron endowment.

scholarly journals ADP-ribosyl cyclase and ryanodine receptors mediate endothelin ETA and ETB receptor-induced renal vasoconstriction in vivo

2008 ◽  
Vol 295 (2) ◽  
pp. F360-F368 ◽  
Author(s):  
Tiffany L. Thai ◽  
William J. Arendshorst
Keyword(s):  
Ryanodine Receptors ◽  
Ruthenium Red ◽  
Sprague Dawley ◽  
Renal Vasculature ◽  
Receptor Stimulation ◽  
Renal Vasoconstriction ◽  
Adp Ribosyl Cyclase ◽  
Etb Receptor ◽  
Rats And Mice

ADP-ribosyl cyclase (ADPR cyclase) and ryanodine receptors (RyR) participate in calcium transduction in isolated afferent arterioles. We hypothesized that this signaling pathway is activated by ETA and ETB receptors in the renal vasculature to mediate vasoconstriction in vivo. To test this, we measured acute renal blood flow (RBF) responses to ET-1 in anesthetized rats and mice in the presence and absence of functional ADPR cyclase and/or RyR. Inhibitors of ADPR cyclase (nicotinamide) or RyR (ruthenium red) reduced RBF responses to ET-1 by 44% ( P < 0.04 for both) in Sprague-Dawley rats. Mice lacking the predominant form of ADPR cyclase (CD38−/−) had RBF responses to ET-1 that were 47% weaker than those seen in wild-type mice ( P = 0.01). Selective ETA receptor stimulation (ET-1+BQ788) produced decreases in RBF that were attenuated by 43 and 56% by nicotinamide or ruthenium red, respectively ( P < 0.02 for both). ADPR cyclase or RyR inhibition also reduced vasoconstrictor effects of the ETB receptor agonist sarafotoxin 6c (S6c; 77 and 54%, respectively, P < 0.02 for both). ETB receptor stimulation by ET-1 + the ETA receptor antagonist BQ123 elicited responses that were attenuated by 59 and 60% by nicotinamide and ruthenium red, respectively ( P < 0.01 for both). Nicotinamide attenuated RBF responses to S6c by 54% during inhibition of nitric oxide synthesis ( P = 0.001). We conclude that in the renal microcirculation in vivo 1) ET-1-induced vasoconstriction is mediated by ADPR cyclase and RyR; 2) both ETA and ETB receptors activate this pathway; and 3) ADPR cyclase participates in ETB receptor signaling independently of NO.

Characterization of type A endothelin receptors in cultured human myometrial cells

1995 ◽  
Vol 268 (5) ◽  
pp. E825-E831 ◽  
Author(s):  
V. Heluy ◽  
M. Breuiller-Fouche ◽  
F. Cavaille ◽  
T. Fournier ◽  
F. Ferre
Keyword(s):  
Inositol Phosphate ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Binding Studies ◽  
Myometrial Cells ◽  
Cells In Culture ◽  
Competition Binding ◽  
Half Maximal Effective Concentration ◽  
Eta Receptor ◽  
Etb Receptor

The aim of the present study was to characterize endothelin (ET)-receptors in human myometrial cells in culture. 125I-labeled ET-1 binding to myometrial cells was specific and saturable, with a dissociation constant of 64.2 +/- 12.8 pM. Competition binding studies showed the following order of potency: ET-1 > ET-3, which is consistent with the presence of the ETA receptor subtype. FR-139317 and BQ-123, two ETA antagonists, both inhibited 125I-ET-1 binding. BQ-123 only elicited a partial inhibition. The fraction resistant to BQ-123 did not represent the ETB receptor subtype, since no specific 125I-ET-3 binding could be detected. ET-1 and ET-3 were found to stimulate [3H]inositol phosphate (IP) accumulation in cultured myometrial cells, with corresponding half-maximal effective concentration values of 0.26 +/- 0.04 and 87 +/- 17 nM, respectively. Both ETA antagonists inhibited ET-1-induced accumulation of [3H]IP. BQ-123 was only a partial inhibitor, whereas FR-139317 totally suppressed ET-1-stimulated production of [3H]IP. We conclude that human myometrial cells in culture exclusively possess ETA receptor subtypes coupled to phospholipase C.

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