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.

ADP-ribosyl cyclase and ryanodine receptor activity contribute to basal renal vasomotor tone and agonist-induced renal vasoconstriction in vivo

2007 ◽  
Vol 293 (4) ◽  
pp. F1107-F1114 ◽  
Author(s):  
Tiffany L. Thai ◽  
Susan K. Fellner ◽  
William J. Arendshorst
Keyword(s):  
Ryanodine Receptors ◽  
Ruthenium Red ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Vasomotor Tone ◽  
Renal Vasoconstriction ◽  
Adp Ribosyl Cyclase ◽  
Sprague Dawley Rats ◽  
G Protein Coupled

An important role for the enzyme ADP-ribosyl cyclase (ADPR cyclase) and its downstream targets, the ryanodine receptors (RyR), is emerging for a variety of vascular systems. We hypothesized that the ADPR cyclase/RyR pathway contributes to regulation of renal vasomotor tone in vivo. To test this, we continuously measured renal blood flow (RBF) in anesthetized Sprague-Dawley rats. Infusion of the ADPR cyclase inhibitor nicotinamide intrarenally at low doses inhibits angiotensin II (ANG II)- and norepinephrine (NE)-induced vasoconstriction by 72 and 67%, respectively ( P < 0.001). RBF studies in rats were extended to mice lacking the predominant form of ADPR cyclase (CD38). Acute renal vasoconstrictor responses to ANG II and NE are impaired by 59 and 52%, respectively, in anesthetized CD38−/− mice compared with wild-type controls ( P < 0.05). Intrarenal injection of the RyR activator FK506 decreases RBF by 22% ( P > 0.03). Furthermore, RyR inhibition with ruthenium red attenuates ANG II and NE responses by 50 and 59%, respectively ( P ≤ 0.01). Given at higher doses, nicotinamide increases basal RBF by 22% ( P > 0.001). Non-receptor-mediated renal vasoconstriction by L-type voltage-gated Ca2+ channels is also dependent on ADPR cyclase and RyRs. Nicotinamide and ruthenium red inhibit constriction by the L-type channel agonist BAY K 8644 by 59% ( P > 0.02) and 63% ( P > 0.001). We conclude that 1) ADPR cyclase activity contributes to regulation of renal vasomotor tone under resting conditions, 2) renal vasoconstriction induced by G protein-coupled receptor agonists ANG II and NE is mediated in part by ADPR cyclase and RyRs, and 3) ADPR cyclase and RyRs participate in L-type channel-mediated renal vasoconstriction in vivo.

scholarly journals Thromboxane-induced renal vasoconstriction is mediated by the ADP-ribosyl cyclase CD38 and superoxide anion

2013 ◽  
Vol 305 (6) ◽  
pp. F830-F838 ◽  
Author(s):  
Nicholas G. Moss ◽  
Paul A. Vogel ◽  
Tayler E. Kopple ◽  
William J. Arendshorst
Keyword(s):  
Superoxide Anion ◽  
Ryanodine Receptors ◽  
Receptor Activation ◽  
Renal Vasoconstriction ◽  
Tp Receptor ◽  
Adp Ribosyl Cyclase ◽  
Tp Receptors ◽  
Renal Vascular

The present renal hemodynamic study tested the hypothesis that CD38 and superoxide anion (O2·−) participate in the vasoconstriction produced by activation of thromboxane prostanoid (TP) receptors in the mouse kidney. CD38 is the major mammalian ADP-ribosyl cyclase contributing to vasomotor tone through the generation of cADP-ribose, a second messenger that activates ryanodine receptors to release Ca2+ from the sarcoplasmic reticulum in vascular smooth muscle cells. We evaluated whether the stable thromboxane mimetic U-46619 causes less pronounced renal vasoconstriction in CD38-deficient mice and the involvement of O2·− in U-46619-induced renal vasoconstriction. Our results indicate that U-46619 activation of TP receptors causes renal vasoconstriction in part by activating cADP-ribose signaling in renal resistance arterioles. Based on maximal renal blood flow and renal vascular resistance responses to bolus injections of U-46619, CD38 contributes 30–40% of the TP receptor-induced vasoconstriction. We also found that the antioxidant SOD mimetic tempol attenuated the magnitude of vasoconstriction by U-46619 in both groups of mice, suggesting mediation by O2·−. The degree of tempol blockage of U-46619-induced renal vasoconstriction was greater in wild-type mice, attenuating renal vasoconstriction by 40% compared with 30% in CD38-null mice. In other experiments, U-46619 rapidly stimulated O2·− production (dihydroethidium fluorescence) in isolated mouse afferent arterioles, an effect abolished by tempol. These observations provide the first in vivo demonstration of CD38 and O2·− involvement in the vasoconstrictor effects of TP receptor activation in the kidney and in vitro evidence for TP receptor stimulation of O2·− production by the afferent arteriole.

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.

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.

Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans

2002 ◽  
Vol 93 (6) ◽  
pp. 2112-2121 ◽  
Author(s):  
Gunvor Ahlborg ◽  
Jonas Lindström
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Healthy Subjects ◽  
Receptor Blockade ◽  
Receptor Stimulation ◽  
Renal Vasoconstriction ◽  
Arterial Blood ◽  
Etb Receptor

Cardiovascular diseases are characterized by insulin resistance and elevated endothelin (ET)-1 levels. Furthermore, ET-1 induces insulin resistance. To elucidate this mechanism, six healthy subjects were studied during a hyperinsulinemic euglycemic clamp during infusion of (the ET-1 precursor) big ET-1 alone or after ETA- or ETB-receptor blockade. Insulin levels rose after big ET-1 with or without the ETB antagonist BQ-788 ( P < 0.05) but were unchanged after the ETA antagonist BQ-123 + big ET-1. Infused glucose divided by insulin fell after big ET-1 with or without BQ-788 ( P < 0.05). Insulin and infused glucose divided by insulin values were normalized by ETA blockade. Mean arterial blood pressure rose during big ET-1 with or without BQ-788 ( P < 0.001) but was unchanged after BQ-123. Skeletal muscle, splanchnic, and renal blood flow responses to big ET-1 were abolished by BQ-123. ET-1 levels rose after big ET-1 ( P< 0.01) in a similar way after BQ-123 or BQ-788, despite higher elimination capacity after ETA blockade. In conclusion, ET-1-induced reduction in insulin sensitivity and clearance as well as splanchnic and renal vasoconstriction are ETA mediated. ETA-receptor stimulation seems to inhibit the conversion of big ET-1 to ET-1.

Effects of chloride channel blockers on rat renal vascular responses to angiotensin II and norepinephrine

2004 ◽  
Vol 286 (2) ◽  
pp. F323-F330 ◽  
Author(s):  
Joen Steendahl ◽  
Niels-Henrik Holstein-Rathlou ◽  
Charlotte Mehlin Sorensen ◽  
Max Salomonsson
Keyword(s):  
Angiotensin Ii ◽  
Niflumic Acid ◽  
Channel Blockers ◽  
Ang Ii ◽  
Renal Vasculature ◽  
Renal Vasoconstriction ◽  
Electromagnetic Flowmetry ◽  
Control Response ◽  
Renal Vascular

The aim of the present study was to investigate the role of Ca2+-activated Cl- channels in the renal vasoconstriction elicited by angiotensin II (ANG II) and norepinephrine (NE). Renal blood flow (RBF) was measured in vivo using electromagnetic flowmetry. Ratiometric photometry of fura 2 fluorescence was used to estimate intracellular free Ca2+ concentration ([Ca2+]i) in isolated preglomerular vessels from rat kidneys. Renal arterial injection of ANG II (2-4 ng) and NE (20-40 ng) produced a transient decrease in RBF. Administration of ANG II (10-7 M) and NE (5 × 10-6 M) to the isolated preglomerular vessels caused a prompt increase in [Ca2+]i. Renal preinfusion of DIDS (0.6 and 1.25 μmol/min) attenuated the ANG II-induced vasoconstriction to ∼35% of the control response, whereas the effects of NE were unaltered. Niflumic acid (0.14 and 0.28 μmol/min) and 2-[(2-cyclopentenyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1 H-inden-5-yl)oxy]acetic acid (IAA-94; 0.045 and 0.09 μmol/min) did not affect the vasoconstrictive responses of these compounds. Pretreatment with niflumic acid (50 μM) or IAA-94 (30 μM) for 2 min decreased baseline [Ca2+]i but did not change the magnitude of the [Ca2+]i response to ANG II and NE in the isolated vessels. The present results do not support the hypothesis that Ca2+-activated Cl- channels play a crucial role in the hemodynamic effects of ANG II and NE in rat renal vasculature.

Enhanced expression of EGF receptor in a model of salt-sensitive hypertension

2005 ◽  
Vol 289 (2) ◽  
pp. F314-F321 ◽  
Author(s):  
Wei-Zhong Ying ◽  
Paul W. Sanders
Keyword(s):  
Egf Receptor ◽  
Primary Cultures ◽  
Growth Factor Receptor ◽  
Sprague Dawley ◽  
Renal Vasculature ◽  
Downstream Signaling ◽  
Egfr Expression ◽  
Enhanced Expression

Chronic kidney disease in the Dahl/Rapp salt-sensitive (S) rat is related to an arteriolopathic process that occurs following the onset of hypertension and involves vascular smooth muscle cell (VSMC) hyperplasia and luminal constriction. Because previous studies have shown that activation of the epidermal growth factor receptor (EGFR) produces a mitogenic stimulus in VSMC and the EGFR participates integrally in the vasoconstrictor responses of renal arterioles, the present study analyzed the expression of EGFR in these animals. Compared with Sprague-Dawley (SD) rats, renal cortical expression of EGFR was increased in both prehypertensive and hypertensive S rats. Immunohistochemistry using a polyclonal antibody to EGFR demonstrated that EGFR expression was prominent in the renal vasculature, particularly in the media of afferent and efferent arterioles and the aorta of S rats. When examined, primary cultures of VSMC from S rats showed increased expression of EGFR, compared with VSMC from SD and Dahl/Rapp salt-resistant rats. Following addition of EGF, autophosphorylation of the EGFR was enhanced in cells from S rats, as was the downstream signaling events that included activation of p42/44 MAPK and Akt pathways. Thus in vivo and in vitro studies demonstrated augmented expression and functional activity of the EGFR in S rats.

scholarly journals P2X1 receptor blockade inhibits whole kidney autoregulation of renal blood flow in vivo

2010 ◽  
Vol 298 (6) ◽  
pp. F1360-F1368 ◽  
Author(s):  
David A. Osmond ◽  
Edward W. Inscho
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Renal Perfusion ◽  
Receptor Activation ◽  
Receptor Blockade ◽  
Sprague Dawley ◽  
Receptor Stimulation ◽  
Kidney Blood Flow

In vitro experiments demonstrate that P2X1 receptor activation is important for normal afferent arteriolar autoregulatory behavior, but direct in vivo evidence for this relationship occurring in the whole kidney is unavailable. Experiments were performed to test the hypothesis that P2X1 receptors are important for autoregulation of whole kidney blood flow. Renal blood flow (RBF) was measured in anesthetized male Sprague-Dawley rats before and during P2 receptor blockade with PPADS, P2X1 receptor blockade with IP5I, or A1 receptor blockade with DPCPX. Both P2X1 and A1 receptor stimulation with α,β-methylene ATP and CPA, respectively, caused dose-dependent decreases in RBF. Administration of either PPADS or IP5I significantly blocked P2X1 receptor stimulation. Likewise, administration of DPCPX significantly blocked A1 receptor activation to CPA. Autoregulatory behavior was assessed by measuring RBF responses to reductions in renal perfusion pressure. In vehicle-infused rats, as pressure was decreased from 120 to 100 mmHg, there was no decrease in RBF. However, in either PPADS- or IP5I-infused rats, each decrease in pressure resulted in a significant decrease in RBF, demonstrating loss of autoregulatory ability. In DPCPX-infused rats, reductions in pressure did not cause significant reductions in RBF over the pressure range of 100–120 mmHg, but the autoregulatory curve tended to be steeper than vehicle-infused rats over the range of 80–100 mmHg, suggesting that A1 receptors may influence RBF at lower pressures. These findings are consistent with in vitro data from afferent arterioles and support the hypothesis that P2X1 receptor activation is important for whole kidney autoregulation in vivo.

scholarly journals Renal medullary ETB receptors produce diuresis and natriuresis via NOS1

2008 ◽  
Vol 294 (5) ◽  
pp. F1205-F1211 ◽  
Author(s):  
Daisuke Nakano ◽  
Jennifer S. Pollock ◽  
David M. Pollock
Keyword(s):  
Renal Medulla ◽  
Urinary Sodium Excretion ◽  
Receptor Activation ◽  
No Production ◽  
Sprague Dawley ◽  
Receptor Stimulation ◽  
Water Excretion ◽  
Sprague Dawley Rats

Endothelin-1 (ET-1) plays an important role in the regulation of salt and water excretion in the kidney. Considerable in vitro evidence suggests that the renal medullary ETB receptor mediates ET-1-induced inhibition of electrolyte reabsorption by stimulating nitric oxide (NO) production. The present study was conducted to test the hypothesis that NO synthase 1 (NOS1) and protein kinase G (PKG) mediate the diuretic and natriuretic effects of ETB receptor stimulation in vivo. Infusion of the ETB receptor agonist sarafotoxin S6c (S6c: 0.45 μg·kg−1·h−1) in the renal medulla of anesthetized, male Sprague-Dawley rats markedly increased the urine flow (UV) and urinary sodium excretion (UNaV) by 67 and 120%, respectively. This was associated with an increase in medullary cGMP content but did not affect blood pressure. In addition, S6c-induced diuretic and natriuretic responses were absent in ETB receptor-deficient rats. Coinfusion of NG-propyl-l-arginine (10 μg·kg−1·h−1), a selective NOS1 inhibitor, suppressed S6c-induced increases in UV, UNaV, and medullary cGMP concentrations. Rp-8-Br-PET-cGMPS (10 μg·kg−1·h−1) or RQIKIWFQNRRMKWKK-LRK5H-amide (18 μg·kg−1·h−1), a PKG inhibitor, also inhibited S6c-induced increases in UV and UNaV. These results demonstrate that renal medullary ETB receptor activation induces diuretic and natriuretic responses through a NOS1, cGMP, and PKG pathway.

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