Failure to upregulate the adenosine_2Areceptor-epoxyeicosatrienoic acid pathway contributes to the development of hypertension in Dahl salt-sensitive rats

Abstract

Liclican EL, McGiff JC, Falck JR, Carroll MA. Failure to upregulate the adenosine2A receptor-epoxyeicosatrienoic acid pathway contributes to the development of hypertension in Dahl saltsensitive rats. Am J Physiol Renal Physiol 295: F1696 -F1704, 2008. First published October 1, 2008 doi:10.1152/ajprenal.90502.2008.-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 A2AR-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 N G -nitro-L-arginine methyl ester and preconstricted with phenylephrine. Bolus injections of the stable adenosine analog 2-chloroadenosine (2-CA; 0.1-20 g) 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 g of 2-CA, as measured by the reduction in renal perfusion pressure, than that of Dahl SR rats fed a NS diet (Ϫ104 Ϯ 6 vs. Ϫ77 Ϯ 7 mmHg, respectively; P Ͻ 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 Ϯ 6 vs. 104 Ϯ 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 A 2A R-EET pathway in response to salt loading may contribute to the development of salt-sensitive hypertension. epoxyeicosatrienoic acids; kidney; salt-sensitive hypertension SALT SENSITIVITY, as defined by blood pressure elevation in response to a dietary salt load, is not only a causative factor for a subgroup of humans with essential hypertension but also has been reported to be an independent cardiovascular risk factor in patients with hypertension (32). Therefore, understanding the mechanisms that contribute to the development of salt sensitivity and identifying potential therapeutic targets for the management of salt-sensitive hypertension should provide novel approaches to treat elevated blood pressure. Cytochrome P-450 (CYP) epoxygenases play a critical role in moderating salt sensitivity by producing epoxyeicosatrienoic acids (EETs). Capdevila and colleagues (5, 28) established the importance of EETs in antagonizing the pressor effects of high salt (HS) intake. Blood pressure did not increase...

Contributions of A2Aand A2Badenosine receptors in coronary flow responses in relation to the KATPchannel using A2Band A2A/2Bdouble-knockout mice

“…In addition, we have previously demonstrated that the A 2A AR is upregulated in high-salt diet-fed mice compared with normal-salt diet-fed mice (51) and that failure to upregulate the A 2A AR-induced pathway contributes to the development of hypertension (44). Furthermore, a few studies have shown that the A 2B AR is selectively upregulated in ischemic mouse hearts and by hypoxic conditions (3,18) and that differential expression of ARs contributes to the functional heterogeneity of human endothelial cells (21).…”

Adenosine Effects on Renal Function in the Rat: Role of Sodium Intake and Cytochrome P450

“…Nonselective stimulation of P1 receptors with adenosine or selective stimulation of A2a subtype with DPMA induced consistent responses only in rats on an HS diet, possibly depending on enhanced generation of ADO [4,5] and/or on an increased expression ratio of A2R to A1R subtypes [5,6,7,12]. Presumably, on a high-salt intake, the vasodilator A2 prevails over the vasoconstrictor A1, whilst on a low-salt intake the effects of stimulation of both receptor types are in balance.…”

“…In the rat, a high-sodium (HS) intake was reported to increase the intrarenal generation of ADO [4,5] and the A2R/A1R expression ratio [5,6,7]. We found that exogenous ADO increased renal cortical and medullary perfusion in rats on HS but not on low-sodium (LS) diets [8].…”

“…Stimulation of A2R is known to activate the endothelial and possibly also tubular cytochrome P450 (CYP450)-dependent metabolism of arachidonic acid [7,11,12,13,14,15]. Since the major active metabolites of the CYP450 pathway - epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid - are both vasoactive and transport inhibitory, they are likely to mediate the post-ADO changes in excretion.…”

Nitric Oxide as an Initiator of Brain Lesions During the Development of Alzheimer Disease

“…One of these factors is almost certainly the hemoprotein cytochrome p450 metabolite arachidonic acid, which forms the signaling molecule epoxyeicosatrienoic acid (EET) (Liclican et al 2008). The role of EETs could be particularly important because, in addition to contributing to the maintenance of the basal tone and endothelium-dependent dilation of conduit arteries, it share many vascular protective properties with NO, suggesting that its alteration might be involved in the physiopathology of cardiovascular diseases.…”