Afferent arteriolar vasodilator effect of adenosine predominantly involves adenosine A_2B receptor activation

Abstract

Feng MG, Navar LG. Afferent arteriolar vasodilator effect of adenosine predominantly involves adenosine A2B receptor activation. Am J Physiol Renal Physiol 299: F310 -F315, 2010. First published May 12, 2010 doi:10.1152/ajprenal.00149.2010.-Adenosine is an important paracrine agent regulating renal vascular tone via adenosine A1 and A2 receptors. While A2B receptor message and protein have been localized to preglomerular vessels, functional evidence on the role of A2B receptors in mediating the vasodilator action of adenosine on afferent arterioles is not available. The present study determined the role of A2B receptors in mediating the afferent arteriolar dilation and compared the effects of A2B and A2A receptor blockade on afferent arterioles. We used the rat in vitro blood-perfused juxtamedullary nephron technique combined with videomicroscopy. Single afferent arterioles of Sprague-Dawley rats were visualized and superfused with solutions containing adenosine or adenosine A2 receptor agonist (CV-1808) along with adenosine A2B and A2A receptor blockers. Adenosine (10 mol/l) caused modest constriction and subsequent superfusion with SCH-58261 (SCH), an A2A receptor blocker, at concentrations up 10 mol/l elicited only slight additional decreases in afferent arteriolar diameter with maximum effect at a concentration of 1 mol/l (Ϫ11.0 Ϯ 2.5%, n ϭ 6, P Ͻ 0.05). However, superfusion of adenosine-treated vessels with MRS-1754 (MRS), an A2B receptor blocker, elicited greater decreases in afferent arteriolar diameter (Ϫ26.0 Ϯ 4.7%, n ϭ 5, P Ͻ 0.01). SCH did not significantly augment the adenosine-mediated afferent constriction elicited by MRS; however, adding MRS after SCH caused further significant vasoconstriction. Superfusion with CV-1808 dilated afferent arterioles (17.2 Ϯ 2.4%, n ϭ 6, P Ͻ 0.01). This effect was markedly attenuated by MRS (Ϫ22.6 Ϯ 2.0%, n ϭ 5, P Ͻ 0.01) but only slightly reduced by SCH (Ϫ9.0 Ϯ 1.1%, n ϭ 5, P Ͻ 0.05) and completely prevented by adding MRS after SCH (Ϫ24.7 Ϯ 1.8%, n ϭ 5, P Ͻ 0.01). These results indicate that, while both A2A and A2B receptors are functionally expressed in juxtamedullary afferent arterioles, the powerful vasodilating action of adenosine predominantly involves A2B receptor activation, which counteracts A1 receptor-mediated vasoconstriction. adenosine receptor antagonists; renal microcirculation; vascular biology; afferent arterioles; kidney ADENOSINE IS AN ENDOGENOUS purine nucleoside derived from the degradation of ATP/AMP and serves as a paracrine agent influencing many physiological processes. Four subtypes of adenosine receptors have been identified: A 1 , A 2A , A 2B , and A 3 ; all are guanine nucleotide-binding protein (G)-coupled receptors (6,15,25,26,28,29), which are characterized by their capacity to either increase or decrease intracellular cAMP levels (13). A 2A and A 2B receptors are coupled to G s protein signaling and mediate biological effects opposite to A 1 and A 3 receptors, which are coupled to G i protein signaling (13). All four subtypes of aden...

2′-AMP and 3′-AMP Inhibit Proliferation of Preglomerular Vascular Smooth Muscle Cells and Glomerular Mesangial Cells via A2B Receptors

“…For example, A 2B receptors are strongly expressed in rat preglomerular microvessels (Jackson et al, 2002), and studies in A 2B receptor knockout mice provide striking evidence that adenosine (Grenz et al, 2007a,b) via activation of renovascular A 2B receptors mediates renal ischemic preconditioning and protects the kidney from ischemia/reperfusion injury. Moreover, renovascular A 2B receptors dampen the hypoxia-induced vascular leak in mouse kidneys , and recent studies using the rat in vitro blood-perfused juxtamedullary nephron technique show that A 2B receptors in the afferent arteriole cause profound vasodilation and counteract A 1 receptor-induced vasoconstriction (Feng and Navar, 2010). The fact that 2Ј,3Ј-cAMP, 2Ј-AMP, and 3Ј-AMP can be metabolized to adenosine and can thereby activate renovascular A 2B receptors suggests that the 2Ј,3Ј-cAMP-adenosine pathway not only may regulate vascular and glomerular structure via antiproliferative effects but may also participate in renal protection and regulation of renovascular tone.…”

Purinergic signalling in the kidney in health and disease

“…Both A 2A and A 2B receptors are functionally expressed in juxtamedullary afferent arterioles, and the dilator effects of adenosine are predominantly mediated by A 2B receptors, which counteract A 1 receptor-mediated vasoconstriction [84].…”

Endogenous adenosine contributes to renal sympathetic neurotransmission via postjunctional A1receptor-mediated coincident signaling

“…Our results are consistent with the Westfall mechanism because DPCPX attenuates vasoconstrictor responses to RSNS, but not to exogenous NE, and exogenous NE does not siginificantly increase adenosine production by the isolated, perfused kidney. However, it is also conceivable that the differential effects of A 1 receptor antagonism on responses to exogenous NE vs. RSNS could be due to relatively selective expression of vasoconstrictor A 1 receptors in the postjunctional surface of the neuroeffector junction vs. relatively selective expression of vasodilatory A 2A (4) and A 2B (15) receptors (which would counteract the effects of A 1 receptors) in the noninnervated vascular muscle cell membranes in the kidney microcirculation. Because exogenously administered NE would mostly engage noninnervated vascular smooth muscle cell surfaces, whereas NE released from sympathetic nerve terminals would stimulate mostly innervated vascular smooth muscle cell surfaces, this too could explain the fact that DPCPX attenuates responses to RSNS, but not to exogenous NE.…”