Role of Adenosine A₁Receptor in Angiotensin II- and Norepinephrine-Induced Renal Vasoconstriction

Abstract

We investigated the contributions of adenosine A 1 receptors to angiotensin II-and norepinephrine-induced renal vasoconstriction. Intrarenal administrations of angiotensin II (3, 10, and 30 ng) or norepinephrine (100 and 500 ng) produced dose-dependent renal vasoconstriction in anesthetized dogs. Under resting conditions, angiotensin II (30 ng) and norepinephrine (500 ng) significantly decreased renal blood flow by Ϫ43 Ϯ 3 and Ϫ19 Ϯ 2%, respectively (n ϭ 21). Intra-arterial infusion of adenosine (5 g/kg/min) significantly augmented renal blood flow responses to both angiotensin II and norepinephrine (Ϫ64 Ϯ 4 and Ϫ45 Ϯ 14%, n ϭ 7). Renal blood flow responses to angiotensin II and norepinephrine were also augmented by inhibition of cellular uptake of adenosine with dipyridamole (10 g/kg/min, n ϭ 6). Blockade of adenosine A 1 receptors with 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902; 10 g/kg/min) did not alter basal renal blood flow but significantly attenuated angiotensin II-and norepinephrine-induced renal vasoconstriction (Ϫ34 Ϯ 6 and Ϫ9 Ϯ 3%, n ϭ 7). Furthermore, KW-3902 completely prevented augmentation of renal blood flow responses to angiotensin II and norepinephrine produced by adenosine or dipyridamole (n ϭ 7 and 6, respectively). Administrations of angiotensin II (30 ng) or norepinephrine (500 ng) into the common carotid artery significantly decreased carotid blood flow by Ϫ20 Ϯ 5 and Ϫ41 Ϯ 10%, respectively; however, neither adenosine (5 g/kg/min) nor KW-3902 (10 g/kg/min) affected the carotid blood flow responses to angiotensin II and norepinephrine (n ϭ 5, respectively). Adenosine concentrations in dialysates were not significantly changed by administrations of angiotensin II (from 19 Ϯ 3 to 24 Ϯ 4 nM, n ϭ 6) or norepinephrine (from 16 Ϯ 3 to 19 Ϯ 3 nM, n ϭ 6). These results suggest that basal interstitial adenosine levels influence both angiotensin II and norepinephrine-induced vasoconstriction via A 1 receptors in the kidney but not in the area drained by the common carotid artery. The responses of adenosine to angiotensin II-and norepinephrine-induced renal vasoconstriction may not be mediated through de novo intrarenal adenosine accumulation due to angiotensin II-and norepinephrine-induced renal vasoconstriction.Adenosine exerts a critical role in the paracrine regulation of renal hemodynamics (Navar et al., 1996;Siragy and Linden, 1996;Miura et al., 1999;Nayeem et al., 1999;Zou et al., 1999;Jackson and Dubey, 2001). Substantial experimental evidence supports the existence of a synergistic interaction between adenosine and the renin-angiotensin system in regulating renal hemodynamics (Hall et al., 1985;Hall and Granger, 1986;Wang et al., 1992;Munger and Jackson, 1994;Navar et al., 1996;Traynor et al., 1998). Early studies showed that suppression of the renin-angiotensin system by feeding a high-sodium diet (Osswald et al., 1975) or administration of an angiotensin-converting enzyme inhibitor (Hall et al., 1985) blunts the renal vasoconstrictor action of adenosine. Micropuncture stu...

Attenuated renovascular constrictor responses to angiotensin II in adenosine 1 receptor knockout mice

“…Studies from our laboratory have shown that the constrictor effect of ANG II in isolated rabbit afferent arterioles was blocked by ϳ50% when the A1AR inhibitor DPCPX was present in the bath (17), a finding that was reproduced in the present studies in mouse afferent arterioles. In confirmation of an earlier observation, a recent study in dogs showed that the reduction in RBF caused by ANG II was augmented by intrarenal infusion of adenosine and attenuated by the A1AR antagonist KW-3902 (1,6). The present study is the first to demonstrate that the vasoconstricting effects of acute changes in plasma ANG II levels are attenuated in animals with a life-long absence of A1AR.…”

Role of Interstitial ATP and Adenosine in the Regulation of Renal Hemodynamics and Microvascular Function

“…Adenosine and ATP on RBF Measurements of total RBF in the whole kidney have demonstrated an effect of exogenously administered adenosine on RBF characterized by an initial transient renal vasoconstriction that wanes and becomes supplanted by a gradual vasodilation (20,66,67). Churchill and Bidani (68) observed that intravenous infusion of an adenosine A1 receptor agonist, N 6 -cyclohexyl adenosine, decreased renal plasma flow in anesthetized rats.…”

“…However, this hypothesis has remained controversial because systemic administration of adenosine antagonists does not block RBF or glomerular filtration rate (GFR) autoregulation (94,95). Furthermore, although the TGF mediator must exert selective actions on preglomerular arterioles (20,21), several studies have demonstrated that adenosine or adenosine A1 receptor agonists elicit significant vasoconstriction of efferent arterioles (13,18) and vasa recta (96). It is also recognized that TGF-mediated changes in afferent arteriolar resistance are sustained for long periods (21,22).…”

“…It is also recognized that TGF-mediated changes in afferent arteriolar resistance are sustained for long periods (21,22). In contrast, adenosine elicits transient vasoconstriction in the kidney that within a few minutes spontaneously abates (20,66,67). Thus, adenosine-mediated vasoconstriction would likely wane as the TGF signal intensity increased.…”

“…In the mid-1960s, several investigators began to investigate the effects of intrarenal arterial infusion of ATP on renal hemodynamics and function (12). Importantly, although ATP can be metabolized via several biochemical pathways that lead to the formation of adenosine, renal hemodynamic responses to ATP are different from those elicited by adenosine (3,(13)(14)(15)(16)(17)(18)(19)(20)(21). Recent studies provide convincing evidence that specific P2 receptor activation by locally released extracellular ATP influences renal microvascular function (3,19,(22)(23)(24)(25)(26)(27)(28).…”