Failure to upregulate the adenosine2A receptor- epoxyeicosatrienoic acid pathway contributes to the development of hypertension in Dahl salt-sensitive rats

Elvira L. Liclican, John C. McGiff, J R Falck, Mairéad A. Carroll

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Adenosine-activated renovascular dilatation in Sprague-Dawley (SD) rats is mediated by stimulating adenosine2A receptors (A2AR), which is linked to epoxyeicosatrienoic acid (EET) synthesis. The A 2AR-EET pathway is upregulated by high salt (HS) intake in normotensive SD rats. Because this pathway is antipressor, we examined the role of the A2AR-EET pathway in Dahl salt-sensitive (SS) rats. Male Dahl salt-resistant (SR) and SS rats were fed either HS (8.0% NaCl) or normal salt (NS; 0.4% NaCl) diet for 7 days. On day 8, isolated kidneys were perfused with Krebs-Henseleit buffer containing indomethacin and NG-nitro-L- arginine methyl ester and preconstricted with phenylephrine. Bolus injections of the stable adenosine analog 2-chloroadenosine (2-CA; 0.1-20 μg) elicited dose-dependent dilation in both Dahl SR and SS rats. Dahl SR rats fed a HS diet demonstrated a greater renal vasodilator response to 10 μg of 2-CA, as measured by the reduction in renal perfusion pressure, than that of Dahl SR rats fed a NS diet (-104 ± 6 vs. -77 ± 7 mmHg, respectively; P < 0.05). In contrast, Dahl SS rats did not exhibit a difference in the vasodilator response to 2-CA whether fed NS or HS diet (96 ± 6 vs. 104 ± 13 mmHg in NS- and HS-fed rats, respectively). In Dahl SR but not Dahl SS rats, HS intake significantly increased purine flux, augmented the protein expression of A2AR and the cytochrome P-450 2C23 and 2C11 epoxygenases, and elevated the renal efflux of EETs. Thus the Dahl SR rat is able to respond to HS intake by recruiting EET formation, whereas the Dahl SS rat appears to have exhausted its ability to increase EET synthesis above the levels observed on NS intake, and this inability of Dahl SS rats to upregulate the A2AR-EET pathway in response to salt loading may contribute to the development of salt-sensitive hypertension.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume295
Issue number6
DOIs
StatePublished - Dec 2008

Fingerprint

Inbred Dahl Rats
Up-Regulation
Salts
Hypertension
Acids
Diet
Kidney
Vasodilator Agents
Adenosine
Sprague Dawley Rats
Dilatation
2-Chloroadenosine
NG-Nitroarginine Methyl Ester
Phenylephrine

Keywords

  • Epoxyeicosatrienoic acids
  • Kidney
  • Salt-sensitive hypertension

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Failure to upregulate the adenosine2A receptor- epoxyeicosatrienoic acid pathway contributes to the development of hypertension in Dahl salt-sensitive rats. / Liclican, Elvira L.; McGiff, John C.; Falck, J R; Carroll, Mairéad A.

In: American Journal of Physiology - Renal Physiology, Vol. 295, No. 6, 12.2008.

Research output: Contribution to journalArticle

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abstract = "Adenosine-activated renovascular dilatation in Sprague-Dawley (SD) rats is mediated by stimulating adenosine2A receptors (A2AR), which is linked to epoxyeicosatrienoic acid (EET) synthesis. The A 2AR-EET pathway is upregulated by high salt (HS) intake in normotensive SD rats. Because this pathway is antipressor, we examined the role of the A2AR-EET pathway in Dahl salt-sensitive (SS) rats. Male Dahl salt-resistant (SR) and SS rats were fed either HS (8.0{\%} NaCl) or normal salt (NS; 0.4{\%} NaCl) diet for 7 days. On day 8, isolated kidneys were perfused with Krebs-Henseleit buffer containing indomethacin and NG-nitro-L- arginine methyl ester and preconstricted with phenylephrine. Bolus injections of the stable adenosine analog 2-chloroadenosine (2-CA; 0.1-20 μg) elicited dose-dependent dilation in both Dahl SR and SS rats. Dahl SR rats fed a HS diet demonstrated a greater renal vasodilator response to 10 μg of 2-CA, as measured by the reduction in renal perfusion pressure, than that of Dahl SR rats fed a NS diet (-104 ± 6 vs. -77 ± 7 mmHg, respectively; P < 0.05). In contrast, Dahl SS rats did not exhibit a difference in the vasodilator response to 2-CA whether fed NS or HS diet (96 ± 6 vs. 104 ± 13 mmHg in NS- and HS-fed rats, respectively). In Dahl SR but not Dahl SS rats, HS intake significantly increased purine flux, augmented the protein expression of A2AR and the cytochrome P-450 2C23 and 2C11 epoxygenases, and elevated the renal efflux of EETs. Thus the Dahl SR rat is able to respond to HS intake by recruiting EET formation, whereas the Dahl SS rat appears to have exhausted its ability to increase EET synthesis above the levels observed on NS intake, and this inability of Dahl SS rats to upregulate the A2AR-EET pathway in response to salt loading may contribute to the development of salt-sensitive hypertension.",
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AB - Adenosine-activated renovascular dilatation in Sprague-Dawley (SD) rats is mediated by stimulating adenosine2A receptors (A2AR), which is linked to epoxyeicosatrienoic acid (EET) synthesis. The A 2AR-EET pathway is upregulated by high salt (HS) intake in normotensive SD rats. Because this pathway is antipressor, we examined the role of the A2AR-EET pathway in Dahl salt-sensitive (SS) rats. Male Dahl salt-resistant (SR) and SS rats were fed either HS (8.0% NaCl) or normal salt (NS; 0.4% NaCl) diet for 7 days. On day 8, isolated kidneys were perfused with Krebs-Henseleit buffer containing indomethacin and NG-nitro-L- arginine methyl ester and preconstricted with phenylephrine. Bolus injections of the stable adenosine analog 2-chloroadenosine (2-CA; 0.1-20 μg) elicited dose-dependent dilation in both Dahl SR and SS rats. Dahl SR rats fed a HS diet demonstrated a greater renal vasodilator response to 10 μg of 2-CA, as measured by the reduction in renal perfusion pressure, than that of Dahl SR rats fed a NS diet (-104 ± 6 vs. -77 ± 7 mmHg, respectively; P < 0.05). In contrast, Dahl SS rats did not exhibit a difference in the vasodilator response to 2-CA whether fed NS or HS diet (96 ± 6 vs. 104 ± 13 mmHg in NS- and HS-fed rats, respectively). In Dahl SR but not Dahl SS rats, HS intake significantly increased purine flux, augmented the protein expression of A2AR and the cytochrome P-450 2C23 and 2C11 epoxygenases, and elevated the renal efflux of EETs. Thus the Dahl SR rat is able to respond to HS intake by recruiting EET formation, whereas the Dahl SS rat appears to have exhausted its ability to increase EET synthesis above the levels observed on NS intake, and this inability of Dahl SS rats to upregulate the A2AR-EET pathway in response to salt loading may contribute to the development of salt-sensitive hypertension.

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