Pollock, D.M.

Schneider, M.P.

English

PubMed

David M. Pollock

Markus P. Schneider

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Clarifying Endothelin Type B Receptor Function

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       Pollock, D.M. and Schneider, M.P. (2006) Clarifying endothelin type B receptor function. Hypertension, 48 (2). pp. 211-212. ISSN 0194-911X  http://eprints.gla.ac.uk/54697/  Deposited on: 8 December 2011   Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk David M. Pollock and Markus P. SchneiderClarifying Endothelin Type B Receptor FunctionISSN: 1524-4563 Copyright © 2006 American Heart Association. All rights reserved. Print ISSN: 0194-911X. Online72514Hypertension is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TXdoi: 10.1161/01.HYP.0000229908.62191.6e2006, 48:211-212: originally published online June 26, 2006Hypertension http://hyper.ahajournals.org/content/48/2/211located on the World Wide Web at: The online version of this article, along with updated information and services, ishttp://www.lww.com/reprintsReprints: Information about reprints can be found online at   journalpermissions@lww.com410-528-8550. E-mail: Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters  http://hyper.ahajournals.org//subscriptions/Subscriptions: Information about subscribing to Hypertension is online at  at GLASGOW UNIV LIB on December 8, 2011http://hyper.ahajournals.org/Downloaded from Clarifying Endothelin Type B Receptor FunctionDavid M. Pollock, Markus P. SchneiderEndothelin (ET) receptors have become the targets forthe treatment of a variety of cardiovascular disordersand a mixed ET type A (ETA)/ET type B (ETB)receptor antagonist, bosentan, is currently being used to effec-tively treat pulmonary hypertension. An ongoing debate hasrevolved around the question of whether selective ETA receptorblockade would be preferable to using the mixed antagonist. Thefunctional role of ET-1 is complicated by the opposing actions ofthe ETA and ETB receptor in the vasculature, as well as thekidney. ETB receptor function is further complicated by thepresence of vasoconstrictor ETB receptors on vascular smoothmuscle in some vascular beds, whereas ETB receptors onendothelium and renal tubules have vasodilator and natriureticactivities. ETB receptors also serve to clear ET-1 from thecirculation and, thus, minimize vasoconstrictor activity. Despitethe well-recognized effects of ETB receptors to oppose ETA-mediated actions, it is not clear whether blocking both ETA andETB receptors at the same time is detrimental or advantageouscompared with selective ETA blockade. Indeed, ETA selectiveantagonists are also expected to soon receive approval fortreatment of pulmonary hypertension. Although this may indi-cate that both strategies work in pulmonary hypertension, thepros and cons of selective versus mixed antagonists are muchless clear in arterial hypertension and heart and kidney failure.Previous studies have shown that pharmacological blockadeor genetic deficiency of ETB receptors results in salt-sensitivehypertension in rats.1,2 More recent studies have now providedinformation on the location(s) of the ETB receptors responsiblefor this effect. Ahn et al3 demonstrated salt-sensitive hyperten-sion in mice where ET-1 expression was selectively knocked outin the renal collecting duct. It was not clear, however, whetherET-1 originating from the collecting duct acts on ETB receptorsof vascular elements within the renal medulla or in an autocrinefashion on ETB receptors of collecting duct cells. In the currentissue of Hypertension, Bagnall et al4 report that selectivedeletion of the ETB receptor from endothelial cells in mice hasno affect on blood pressure or salt sensitivity despite reducedendothelial-dependent relaxation. The authors conclude thatET-1 more likely acts in an autocrine fashion on collecting ductcells, as opposed to activating endothelial ETB receptors on vasarecta, which could facilitate sodium excretion through an in-crease in medullary perfusion. This conclusion is further sup-ported by reports that ETB receptors inhibit electrolyte reabsorp-tion in vitro.5–7 Strictly speaking, a role for increased medullaryperfusion in the renal response to a high-salt diet mediated by theETB receptor cannot be completely ruled out yet. It is conceiv-able that activation of ETB receptors on tubular cells causes vasarecta to dilate through a “tubulovascular crosstalk” mechanismsimilar to that described previously for buffering angiotensinII–mediated vasoconstriction in the renal medulla and mediatedby NO.8 Although some questions do remain about the precisemechanisms, the studies by Bagnall et al,4 together with previousresults from other groups, indicate a major role for renal tubularETB receptors in mediating ET-1–induced natriuresis.3,4,7In addition to giving new insight into the renal mechanisms,the current study also seems to dramatically reduce the likeli-hood of vascular endothelial ETB receptors mediating salt-sensitive hypertension during systemic ETB receptor blockade.Interestingly, previous cross-transplantation experiments in ETBreceptor–deficient rats showed that salt sensitivity in this modeldepended on the deletion of extrarenal ETB receptors.9 Thisraises the possibility that a yet-unidentified extrarenal ETB receptormay have a protective effect against salt-sensitive hypertension,in addition to the ETB receptor on renal tubular cells.Although it has been assumed for quite some time that theendothelial ETB receptor is responsible for clearing circulatingET-1, the functional ramifications of this concept have beendifficult to discern with other models in rats, such as pharma-cological ETB receptor blockade or ETB receptor deficiency.1,2Endothelial-specific ETB knockout mice have elevated levels ofcirculating ET-1, which provide even more definitive evidencefor a role of ETB receptors on endothelium in clearing ET-1 fromthe circulation. However, it is now also important to realize thatthe resulting elevations in circulating ET-1 do not account for thehypertension produced by pharmacological or genetic disruptionof the ETB receptor as documented previously.1,2 Several labo-ratories have shown that hypertension produced by ETB receptorblockade or high-salt intake in ETB receptor–deficient rats canbe blocked by ETA receptor antagonism.2,10,11 Although anobvious argument is that a lack of ETB receptors displaces ET-1to produce greater ETA receptor–dependent vasoconstriction,this cannot account for the hypertension in these models giventhese new findings. Just because ETA receptor blockade reducesblood pressure in a model of hypertension does not signify thatthe hypertension was produced by increased ETA receptor activa-tion. It is also not clear how a shift of ET-1 from the ETB to theETA receptor could explain the salt dependence of these models.Again, these new results favor a renal mechanism for thesalt-sensitive hypertension observed with ETB receptor blockadeor genetic deficiency of ETB receptors.Although this study represents an important advance in ourunderstanding of how ET-1 controls blood pressure, there are anumber of questions about ETB receptor function that remain. Itshould be noted that control mice in the current study were saltsensitive, and so it will be important to establish that a lack ofThe opinions expressed in this editorial are not necessarily those of theeditors or of the American Heart Association.From the Vascular Biology Center, Medical College of Georgia, Augusta.Correspondence to David M. Pollock, Vascular Biology Center, MedicalCollege of Georgia, Augusta, GA 30912-2500. E-mail dpollock@mcg.edu(Hypertension. 2006;48:211-212.)© 2006 American Heart Association, Inc.Hypertension is available at http://www.hypertensionaha.orgDOI: 10.1161/01.HYP.0000229908.62191.6e211Editorial Commentary at GLASGOW UNIV LIB on December 8, 2011http://hyper.ahajournals.org/Downloaded from endothelial ETB receptors does not result in salt-dependenthypertension in mice with a salt-resistant genetic background.Another issue that no one has yet addressed is whether gastro-intestinal absorption of salt is altered in animals lacking ETBreceptor function. ET-3, which selectively acts on ETB receptors,has been shown previously to inhibit intestinal sodium reabsorp-tion in dogs.12 The precise location of the ETB receptor respon-sible for this effect can now be further investigated with this newmodel or other tissue-specific models. Finally, there is emergingevidence for ETB receptor influence within the sympatheticnervous system that may participate in short-term blood pressurecontrol.13Throughout the literature, there are many references to thephenomenon known as “endothelial dysfunction.” It is quitecommonly referred to as a reduced vasodilator response toacetylcholine administration, and so it is clear that we must nowinclude reduced ETB receptor function as one possible cause ofthe dysfunction. Even more intriguing, reduced endothelial-dependent vasodilation in endothelial cell ETB receptor knockoutmice does not translate into hypertension. These results addimportant new information to the ongoing debate of whetherendothelial dysfunction is a cause or a consequence of hyper-tension. Similarly, vascular overexpression of ET-1 in mice hasbeen shown to lead to endothelial dysfunction in the absence ofhypertension.14 Whether the absence of hypertension is specificto the endothelial dysfunction induced by increased expressionof ET-1 or deletion of endothelial ETB receptors remains to bedetermined. It will also be important to investigate what changesin ETA receptor activity, if any, occur within the vascular systemwhen the ETB receptor is absent from the endothelium.In summary, the work of Bagnall et al4 represents an impor-tant advance in the understanding of how ET-1 controls bloodpressure and the response to salt and provides a valuable newtool for exploring ETB receptor function. Because so much focushas been on the negative effects of ETA receptor activation incardiovascular disease, function of the ETB receptor on theendothelium has been a relatively underinvestigated aspect ofthe ET system. Although many questions remain, the work fromthis group and others, including results with the collectingduct-specific knockout mice, clearly establish an important rolefor renal epithelial ETB receptors in regulating salt excretion.This study should provide an impetus for more focus on ETBreceptor function in control of vascular function and alsorepresents another important piece of the puzzle that willeventually answer the question as to when and where ETBreceptor blockade may be helpful or harmful.DisclosuresNone.References1. Gariepy CE, Ohuchi T, Williams SC, Richardson JA, Yanagisawa M.Salt-sensitive hypertension in endothelin-B receptor-deficient rats. J ClinInvest. 2000;105:925–933.2. Pollock DM, Pollock JS. Evidence for endothelin involvement in theresponse to high salt. Am J Physiol Renal Physiol. 2001;281:F144–F150.3. Ahn D, Ge Y, Stricklett PK, Gill P, Taylor D, Hughes AK, YanagisawaM, Miller L, Nelson RD, Kohan DE. Collecting duct-specific knockout ofendothelin-1 causes hypertension and sodium retention. J Clin Invest.2004;114:504–511.4. Bagnall AJ, Kelland NF, Gulliver-Sloan F, Davenport AP, Gray GA,Yanagisawa M, Webb DJ, Kotelevtsev YV. Deletion of endothelial cellendothelin B receptors does not affect blood pressure or sensitivity to salt.Hypertension. 2006;48:286–293.5. Gallego MS, Ling BN. Regulation of amiloride-sensitive Na channels byendothelin-1 in distal nephron cells. Am J Physiol. 1996;271:F451–F460.6. Kohan DE, Padilla E, Hughes AK. Endothelin B receptor mediates ET-1effects on cAMP and PGE2 accumulation in rat IMCD. Am J PhysiolRenal Physiol. 1993;265:F670–F676.7. Plato CF, Pollock DM, Garvin JL. Endothelin inhibits thick ascendinglimb chloride flux via ETB receptor-mediated NO release. Am J PhysiolRenal Physiol. 2000;279:F326–F333.8. Dickhout JG, Mori T, Cowley AW Jr. Tubulovascular nitric oxidecrosstalk: buffering of angiotensin II-induced medullary vasoconstriction.Circ Res. 2002;91:487–493.9. Ohkita M, Wang Y, Nguyen ND, Tsai YH, Williams SC, Wiseman RC,Killen PD, Li S, Yanagisawa M, Gariepy CE. Extrarenal ETB plays asignificant role in controlling cardiovascular responses to high dietarysodium in rats. Hypertension. 2005;45:940–946.10. Fryer RM, Rakestraw PA, Banfor PN, Cox BF, Opgenorth TJ, ReinhartGA. Blood pressure regulation by ETA and ETB receptors in conscious,telemetry-instrumented mice and role of ETA in hypertension produced byselective ETB blockade. Am J Physiol Heart Circ Physiol. 2006;290:H2554–H2559.11. Elmarakby AA, Dabbs Loomis E, Pollock JS, Pollock DM. ETA receptorblockade attenuates hypertension and decreases reactive oxygen speciesin ETB receptor-deficient rats. J Cardiovasc Pharmacol. 2004;44:S7–S10.12. Chowdhury MR, Uemura N, Suzuki S, Nishida Y, Morita H, Hosomi H.Effects of endothelin on fluid and NaCl absorption across the jejunum inanesthetized dogs. J Cardiovasc Pharmacol. 1993;22(suppl 8):S189–S191.13. Lau YE, Galligan JJ, Kreulen DL, Fink GD. Activation of ETB receptorsincreases superoxide levels in sympathetic ganglia in vivo. Am J PhysiolRegul Integr Comp Physiol. 2006;290:R90–R95.14. Amiri F, Virdis A, Neves MF, Iglarz M, Seidah NG, Touyz RM,Reudelhuber TL, Schiffrin EL. Endothelium-restricted over-expression ofhuman endothelin-1 causes vascular remodeling and endothelial dys-function. Circulation. 2004;110:2233–2240.212 Hypertension August 2006 at GLASGOW UNIV LIB on December 8, 2011http://hyper.ahajournals.org/Downloaded from 

Activation of ETB receptors increases superoxide levels in sympathetic ganglia in vivo.

Blood pressure regulation by ETA and ETB receptors in conscious, telemetry-instrumented mice and role of ETA in hypertension produced by selective ETB blockade.

Collecting duct-specific knockout of endothelin-1 causes hypertension and sodium retention.

Deletion of endothelial cell endothelin B receptors does not affect blood pressure or sensitivity to salt.

Effects of endothelin on fluid and NaCl absorption across the jejunum in anesthetized dogs. J Cardiovasc Pharmacol. 1993;22(suppl 8):S189–S191.

Endothelin B receptor mediates ET-1 effects on cAMP and PGE2 accumulation in rat IMCD.

Endothelin inhibits thick ascending limb chloride flux via ETB receptor-mediated NO release.

Endothelium-restricted over-expression of human endothelin-1 causes vascular remodeling and endothelial dysfunction.

ETA receptor blockade attenuates hypertension and decreases reactive oxygen species in ETB receptor-deficient rats. J Cardiovasc Pharmacol.

Evidence for endothelin involvement in the response to high salt. Am J Physiol Renal Physiol.

Extrarenal ETB plays a significant role in controlling cardiovascular responses to high dietary sodium in rats.

Regulation of amiloride-sensitive Na  channels by endothelin-1 in distal nephron cells.

Salt-sensitive hypertension in endothelin-B receptor-deficient rats.

Tubulovascular nitric oxide crosstalk: buffering of angiotensin II-induced medullary vasoconstriction. Circ Res.

Clarifying endothelin type B receptor function

Enlighten: Publications

 
 
 
 
 
 
 
Pollock, D.M. and Schneider, M.P. (2006) Clarifying endothelin type B 
receptor function. Hypertension, 48 (2). pp. 211-212. ISSN 0194-911X 
 
http://eprints.gla.ac.uk/54697/ 
 
Deposited on: 8 December 2011 
 
 
Enlighten – Research publications by members of the University of Glasgow 
http://eprints.gla.ac.uk 
David M. Pollock and Markus P. Schneider
Clarifying Endothelin Type B Receptor Function
ISSN: 1524-4563 
Copyright © 2006 American Heart Association. All rights reserved. Print ISSN: 0194-911X. Online
72514
Hypertension is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX
doi: 10.1161/01.HYP.0000229908.62191.6e
2006, 48:211-212: originally published online June 26, 2006Hypertension 
http://hyper.ahajournals.org/content/48/2/211
located on the World Wide Web at: 
The online version of this article, along with updated information and services, is
http://www.lww.com/reprints
Reprints: Information about reprints can be found online at 
  
journalpermissions@lww.com
410-528-8550. E-mail: 
Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. 
Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters
  
http://hyper.ahajournals.org//subscriptions/
Subscriptions: Information about subscribing to Hypertension is online at 
 at GLASGOW UNIV LIB on December 8, 2011http://hyper.ahajournals.org/Downloaded from 
Clarifying Endothelin Type B Receptor Function
David M. Pollock, Markus P. Schneider
Endothelin (ET) receptors have become the targets forthe treatment of a variety of cardiovascular disordersand a mixed ET type A (ETA)/ET type B (ETB)
receptor antagonist, bosentan, is currently being used to effec-
tively treat pulmonary hypertension. An ongoing debate has
revolved around the question of whether selective ETA receptor
blockade would be preferable to using the mixed antagonist. The
functional role of ET-1 is complicated by the opposing actions of
the ETA and ETB receptor in the vasculature, as well as the
kidney. ETB receptor function is further complicated by the
presence of vasoconstrictor ETB receptors on vascular smooth
muscle in some vascular beds, whereas ETB receptors on
endothelium and renal tubules have vasodilator and natriuretic
activities. ETB receptors also serve to clear ET-1 from the
circulation and, thus, minimize vasoconstrictor activity. Despite
the well-recognized effects of ETB receptors to oppose ETA-
mediated actions, it is not clear whether blocking both ETA and
ETB receptors at the same time is detrimental or advantageous
compared with selective ETA blockade. Indeed, ETA selective
antagonists are also expected to soon receive approval for
treatment of pulmonary hypertension. Although this may indi-
cate that both strategies work in pulmonary hypertension, the
pros and cons of selective versus mixed antagonists are much
less clear in arterial hypertension and heart and kidney failure.
Previous studies have shown that pharmacological blockade
or genetic deficiency of ETB receptors results in salt-sensitive
hypertension in rats.1,2 More recent studies have now provided
information on the location(s) of the ETB receptors responsible
for this effect. Ahn et al3 demonstrated salt-sensitive hyperten-
sion in mice where ET-1 expression was selectively knocked out
in the renal collecting duct. It was not clear, however, whether
ET-1 originating from the collecting duct acts on ETB receptors
of vascular elements within the renal medulla or in an autocrine
fashion on ETB receptors of collecting duct cells. In the current
issue of Hypertension, Bagnall et al4 report that selective
deletion of the ETB receptor from endothelial cells in mice has
no affect on blood pressure or salt sensitivity despite reduced
endothelial-dependent relaxation. The authors conclude that
ET-1 more likely acts in an autocrine fashion on collecting duct
cells, as opposed to activating endothelial ETB receptors on vasa
recta, which could facilitate sodium excretion through an in-
crease in medullary perfusion. This conclusion is further sup-
ported by reports that ETB receptors inhibit electrolyte reabsorp-
tion in vitro.5–7 Strictly speaking, a role for increased medullary
perfusion in the renal response to a high-salt diet mediated by the
ETB receptor cannot be completely ruled out yet. It is conceiv-
able that activation of ETB receptors on tubular cells causes vasa
recta to dilate through a “tubulovascular crosstalk” mechanism
similar to that described previously for buffering angiotensin
II–mediated vasoconstriction in the renal medulla and mediated
by NO.8 Although some questions do remain about the precise
mechanisms, the studies by Bagnall et al,4 together with previous
results from other groups, indicate a major role for renal tubular
ETB receptors in mediating ET-1–induced natriuresis.3,4,7
In addition to giving new insight into the renal mechanisms,
the current study also seems to dramatically reduce the likeli-
hood of vascular endothelial ETB receptors mediating salt-
sensitive hypertension during systemic ETB receptor blockade.
Interestingly, previous cross-transplantation experiments in ETB
receptor–deficient rats showed that salt sensitivity in this model
depended on the deletion of extrarenal ETB receptors.9 This
raises the possibility that a yet-unidentified extrarenal ETB receptor
may have a protective effect against salt-sensitive hypertension,
in addition to the ETB receptor on renal tubular cells.
Although it has been assumed for quite some time that the
endothelial ETB receptor is responsible for clearing circulating
ET-1, the functional ramifications of this concept have been
difficult to discern with other models in rats, such as pharma-
cological ETB receptor blockade or ETB receptor deficiency.1,2
Endothelial-specific ETB knockout mice have elevated levels of
circulating ET-1, which provide even more definitive evidence
for a role of ETB receptors on endothelium in clearing ET-1 from
the circulation. However, it is now also important to realize that
the resulting elevations in circulating ET-1 do not account for the
hypertension produced by pharmacological or genetic disruption
of the ETB receptor as documented previously.1,2 Several labo-
ratories have shown that hypertension produced by ETB receptor
blockade or high-salt intake in ETB receptor–deficient rats can
be blocked by ETA receptor antagonism.2,10,11 Although an
obvious argument is that a lack of ETB receptors displaces ET-1
to produce greater ETA receptor–dependent vasoconstriction,
this cannot account for the hypertension in these models given
these new findings. Just because ETA receptor blockade reduces
blood pressure in a model of hypertension does not signify that
the hypertension was produced by increased ETA receptor activa-
tion. It is also not clear how a shift of ET-1 from the ETB to the
ETA receptor could explain the salt dependence of these models.
Again, these new results favor a renal mechanism for the
salt-sensitive hypertension observed with ETB receptor blockade
or genetic deficiency of ETB receptors.
Although this study represents an important advance in our
understanding of how ET-1 controls blood pressure, there are a
number of questions about ETB receptor function that remain. It
should be noted that control mice in the current study were salt
sensitive, and so it will be important to establish that a lack of
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Vascular Biology Center, Medical College of Georgia, Augusta.
Correspondence to David M. Pollock, Vascular Biology Center, Medical
College of Georgia, Augusta, GA 30912-2500. E-mail dpollock@mcg.edu
(Hypertension. 2006;48:211-212.)
© 2006 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000229908.62191.6e
211
Editorial Commentary
 at GLASGOW UNIV LIB on December 8, 2011http://hyper.ahajournals.org/Downloaded from 
endothelial ETB receptors does not result in salt-dependent
hypertension in mice with a salt-resistant genetic background.
Another issue that no one has yet addressed is whether gastro-
intestinal absorption of salt is altered in animals lacking ETB
receptor function. ET-3, which selectively acts on ETB receptors,
has been shown previously to inhibit intestinal sodium reabsorp-
tion in dogs.12 The precise location of the ETB receptor respon-
sible for this effect can now be further investigated with this new
model or other tissue-specific models. Finally, there is emerging
evidence for ETB receptor influence within the sympathetic
nervous system that may participate in short-term blood pressure
control.13
Throughout the literature, there are many references to the
phenomenon known as “endothelial dysfunction.” It is quite
commonly referred to as a reduced vasodilator response to
acetylcholine administration, and so it is clear that we must now
include reduced ETB receptor function as one possible cause of
the dysfunction. Even more intriguing, reduced endothelial-
dependent vasodilation in endothelial cell ETB receptor knockout
mice does not translate into hypertension. These results add
important new information to the ongoing debate of whether
endothelial dysfunction is a cause or a consequence of hyper-
tension. Similarly, vascular overexpression of ET-1 in mice has
been shown to lead to endothelial dysfunction in the absence of
hypertension.14 Whether the absence of hypertension is specific
to the endothelial dysfunction induced by increased expression
of ET-1 or deletion of endothelial ETB receptors remains to be
determined. It will also be important to investigate what changes
in ETA receptor activity, if any, occur within the vascular system
when the ETB receptor is absent from the endothelium.
In summary, the work of Bagnall et al4 represents an impor-
tant advance in the understanding of how ET-1 controls blood
pressure and the response to salt and provides a valuable new
tool for exploring ETB receptor function. Because so much focus
has been on the negative effects of ETA receptor activation in
cardiovascular disease, function of the ETB receptor on the
endothelium has been a relatively underinvestigated aspect of
the ET system. Although many questions remain, the work from
this group and others, including results with the collecting
duct-specific knockout mice, clearly establish an important role
for renal epithelial ETB receptors in regulating salt excretion.
This study should provide an impetus for more focus on ETB
receptor function in control of vascular function and also
represents another important piece of the puzzle that will
eventually answer the question as to when and where ETB
receptor blockade may be helpful or harmful.
Disclosures
None.
References
1. Gariepy CE, Ohuchi T, Williams SC, Richardson JA, Yanagisawa M.
Salt-sensitive hypertension in endothelin-B receptor-deficient rats. J Clin
Invest. 2000;105:925–933.
2. Pollock DM, Pollock JS. Evidence for endothelin involvement in the
response to high salt. Am J Physiol Renal Physiol. 2001;281:F144–F150.
3. Ahn D, Ge Y, Stricklett PK, Gill P, Taylor D, Hughes AK, Yanagisawa
M, Miller L, Nelson RD, Kohan DE. Collecting duct-specific knockout of
endothelin-1 causes hypertension and sodium retention. J Clin Invest.
2004;114:504–511.
4. Bagnall AJ, Kelland NF, Gulliver-Sloan F, Davenport AP, Gray GA,
Yanagisawa M, Webb DJ, Kotelevtsev YV. Deletion of endothelial cell
endothelin B receptors does not affect blood pressure or sensitivity to salt.
Hypertension. 2006;48:286–293.
5. Gallego MS, Ling BN. Regulation of amiloride-sensitive Na channels by
endothelin-1 in distal nephron cells. Am J Physiol. 1996;271:F451–F460.
6. Kohan DE, Padilla E, Hughes AK. Endothelin B receptor mediates ET-1
effects on cAMP and PGE2 accumulation in rat IMCD. Am J Physiol
Renal Physiol. 1993;265:F670–F676.
7. Plato CF, Pollock DM, Garvin JL. Endothelin inhibits thick ascending
limb chloride flux via ETB receptor-mediated NO release. Am J Physiol
Renal Physiol. 2000;279:F326–F333.
8. Dickhout JG, Mori T, Cowley AW Jr. Tubulovascular nitric oxide
crosstalk: buffering of angiotensin II-induced medullary vasoconstriction.
Circ Res. 2002;91:487–493.
9. Ohkita M, Wang Y, Nguyen ND, Tsai YH, Williams SC, Wiseman RC,
Killen PD, Li S, Yanagisawa M, Gariepy CE. Extrarenal ETB plays a
significant role in controlling cardiovascular responses to high dietary
sodium in rats. Hypertension. 2005;45:940–946.
10. Fryer RM, Rakestraw PA, Banfor PN, Cox BF, Opgenorth TJ, Reinhart
GA. Blood pressure regulation by ETA and ETB receptors in conscious,
telemetry-instrumented mice and role of ETA in hypertension produced by
selective ETB blockade. Am J Physiol Heart Circ Physiol. 2006;290:
H2554–H2559.
11. Elmarakby AA, Dabbs Loomis E, Pollock JS, Pollock DM. ETA receptor
blockade attenuates hypertension and decreases reactive oxygen species
in ETB receptor-deficient rats. J Cardiovasc Pharmacol. 2004;44:S7–S10.
12. Chowdhury MR, Uemura N, Suzuki S, Nishida Y, Morita H, Hosomi H.
Effects of endothelin on fluid and NaCl absorption across the jejunum in
anesthetized dogs. J Cardiovasc Pharmacol. 1993;22(suppl 8):S189–S191.
13. Lau YE, Galligan JJ, Kreulen DL, Fink GD. Activation of ETB receptors
increases superoxide levels in sympathetic ganglia in vivo. Am J Physiol
Regul Integr Comp Physiol. 2006;290:R90–R95.
14. Amiri F, Virdis A, Neves MF, Iglarz M, Seidah NG, Touyz RM,
Reudelhuber TL, Schiffrin EL. Endothelium-restricted over-expression of
human endothelin-1 causes vascular remodeling and endothelial dys-
function. Circulation. 2004;110:2233–2240.
212 Hypertension August 2006
 at GLASGOW UNIV LIB on December 8, 2011http://hyper.ahajournals.org/Downloaded from 


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Clarifying endothelin type B receptor function

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