Adenosine A_2Areceptor activation attenuates tubuloglomerular feedback responses by stimulation of endothelial nitric oxide synthase

Abstract

Carlström M, Wilcox CS, Welch WJ. Adenosine A2A receptor activation attenuates tubuloglomerular feedback responses by stimulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol 300: F457-F464, 2011. First published November 24, 2010 doi:10.1152/ajprenal.00567.2010.-Adenosine A 2 receptors have been suggested to modulate tubuloglomerular feedback (TGF) responses by counteracting adenosine A1 receptor-mediated vasoconstriction, but the mechanisms are unclear. We tested the hypothesis that A2A receptor activation blunts TGF by release of nitric oxide in the juxtaglomerular apparatus (JGA). Maximal TGF responses were measured in male Sprague-Dawley rats as changes in proximal stopflow pressure (⌬PSF) in response to increased perfusion of the loop of Henle (0 to 40 nl/min) with artificial tubular fluid (ATF). The maximal TGF response was studied after 5 min intratubular perfusion (10 nl/min) with ATF or ATF ϩ A2A receptor agonist (CGS-21680; 10 Ϫ7 mol/l). The interaction with nitric oxide synthase (NOS) isoforms was tested by perfusion with a nonselective NOS inhibitor [N -nitro-Larginine methyl ester hydrochloride (L-NAME); 10Ϫ6 mol/l] alone, and with the A2A agonist. Blood pressure, urine flow, and PSF at 0 nl/min were similar among the groups. The maximal TGF response (⌬PSF) with ATF alone (12.3 Ϯ 0.6 mmHg) was attenuated by selective A2A stimulation (9.5 Ϯ 0.4 mmHg). L-NAME enhanced maximal TGF responses (18.9 Ϯ 0.4 mmHg) significantly more than L-NPA (15.2 Ϯ 0.7 mmHg). Stimulation of A2A receptors did not influence maximal TGF response during nonselective NOS inhibition (19.0 Ϯ 0.4) but attenuated responses during nNOS inhibition (10.3 Ϯ 0.4 mmHg). In conclusion, adenosine A2A receptor activation attenuated TGF responses by stimulation of endothelial NOS (eNOS), presumably in the afferent arteriole. Moreover, NO derived from both eNOS and nNOS in the JGA may blunt TGF responses. adenosine A1 receptor; afferent arterioles; kidney; micropuncture; neuronal nitric oxide synthase; renal microcirculation THE TUBULOGLOMERULAR FEEDBACK (TGF) mechanism is a negative feedback loop that enhances vascular tone of the afferent arteriole when tubular NaCl delivery at the macula densa is increased (44); thus, TGF contributes to renal autoregulation and blood pressure control. Osswald and coworkers (30) first proposed that local generation of adenosine, as a consequence of increased NaCl transport, may elicit TGF-induced afferent arteriole vasoconstriction (30). Adenosine is a paracrine agent that signals through G protein-coupled A 1 , A 2 , and A 3 receptors. The adenosine A 2 receptor family consists of two subtypes, A 2A and the A 2B , that possess a high and a low agonist affinity, respectively (51). Adenylate cyclase, thus cAMP production, is stimulated by the adenosine A 2A and A 2B receptors but inhibited by A 1 and A 3 receptors (51). Studies in genedeficient mice, or with receptor antagonists, have reported that TGF is mediated via activation of adenosine A 1 receptors (3,8,45,46).Adenosine receptor...

Renal afferent arteriolar and tubuloglomerular feedback reactivity in mice with conditional deletions of adenosine 1 receptors

“…Neither the A1AR agonist CHA nor the natural ligand adenosine caused detectable vasoconstriction in vessels of SmCre/A1ARff mice, although adenosine dilated the arterioles at concentrations of Ͼ10 Ϫ6 M presumably through activation of A2AR receptors. Expression of A2AR in afferent arterioles is supported by a number of functional observations (4,18,30). Absence of vasoconstrictor effects indicates a virtually complete loss of functional A1AR in afferent arterioles.…”

Adenosine A1-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment

“…In afferent arterioles from A 1 -deficient mice or during pharmacological inhibition of A 1 -receptors, adenosine only produces vasodilatation (28). Recent studies have demonstrated that A 2 -receptors attenuate TGF responses by counteracting the effects of A 1 -receptors (10,11). Together these findings show that A 2 -receptors buffer A 1 -induced vasoconstriction in preglomerular vessels and thus contribute to regulation of renal hemodynamics and blood pressure.…”

“…The hypertensive responses to L-NAME and ANG II were clearly attenuated in A1 Ϫ/Ϫ mice. Arteriolar contractions to L-NAME (10 Ϫ4 mol/l; 15 min) and cumulative ANG II application (10 Ϫ12 to 10 Ϫ6 mol/l) were lower in A1 Ϫ/Ϫ mice. Simultaneous treatment with tempol (10 Ϫ4 mol/l; 15 min) attenuated arteriolar responses in A1 ϩ/ϩ but not in A1 Ϫ/Ϫ mice, suggesting differences in ROS formation.…”

Estradiol attenuates high glucose-induced endothelial nitrotyrosine: role for neuronal nitric oxide synthase

“…L-NPA is a highly selective nNOS inhibitor that demonstrates ϳ3,150-fold and ϳ150-fold selectivity to nNOS compared with iNOS and eNOS, respectively (49). Several groups have used L-NPA at micromolar concentrations in different systems to demonstrate selective nNOS inhibition (3,11). A recently published study from our group has shown that similar concentrations of L-NPA can indeed inhibit nNOS in the vasculature without affecting eNOS-dependent vascular functions (33).…”