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

Abstract

. Attenuated renovascular constrictor responses to angiotensin II in adenosine 1 receptor knockout mice. Am J Physiol Regul Integr Comp Physiol 285: R44-R49, 2003; 10.1152/ajpregu.00739.2002In the present experiments we examined the renovascular constrictor effects of ANG II in the chronic and complete absence of A1 adenosine receptors (A1AR) using mice with targeted deletion of the A1AR gene. Glomerular filtration rate (GFR) was not different between A1AR ϩ/ϩ and A1AR Ϫ/Ϫ mice under control conditions (450.5 Ϯ 60 vs. 475.2 Ϯ 62.5 l/min) but fell significantly less in A1AR Ϫ/Ϫ mice during infusion of ANG II at 1.5 ng/min (A1AR ϩ/ϩ: 242 Ϯ 32.5 l/min, A1AR Ϫ/Ϫ: 371 Ϯ 42 l/min; P ϭ 0.03). Bolus injection of 1, 10, and 100 ng of ANG II reduced renal blood flow and increased renal vascular resistance significantly more in A1AR ϩ/ϩ than in A1AR Ϫ/Ϫ mice. Perfused afferent arterioles isolated from A1AR ϩ/ϩ mice constricted in response to bath ANG II with an EC 50 of 1.5 Ϯ 0.4 ϫ 10 Ϫ10 mol/l, whereas a right shift in the dose-response relationship with an EC 50 of 7.3 Ϯ 1.2 ϫ 10 Ϫ10 mol/l (P Ͻ 0.05) was obtained in arterioles from A1AR Ϫ/Ϫ mice (P Ͻ 0.05). The expression of AT1A receptor mRNA was not different in kidney RNA from A1AR ϩ/ϩ or A1AR Ϫ/Ϫ mice. We conclude that chronic A1AR deficiency diminishes the effectiveness of ANG II to constrict renal resistance vessels and to reduce GFR. renal blood flow; ultrasonic flowmeter; renal vascular resistance; glomerular filtration rate; perfused arterioles PHENOMENOLOGICAL AND MECHANISTIC aspects of the actions of ANG II and adenosine in the renal vascular bed have been explored in numerous studies. It has been a consistent conclusion from these studies that both agents cause an increase in renal vascular resistance by eliciting vasoconstriction at multiple sites along the renal vasculature. The renal vasoconstrictor response of ANG II is initiated by activation of AT1 receptors while adenosine causes vasoconstriction through the A1 adenosine receptor (A1AR). Several studies suggest that the degree of activation of AT1 or A1A receptors determines the magnitude of the constrictor effects to acute changes in the concentration of the other agonist. The majority of studies exploring such an interaction between adenosine and ANG II have investigated the modifying role of variations of ANG II on the constrictor action of adenosine. The general approach in these studies has been to modulate the renin-angiotensin system, by changing NaCl intake, by utilizing mice with a deletion of the AT1a receptor, or by acutely inhibiting ANG II formation or action with angiotensinconverting enzyme or receptor blockers. The conclusion from these studies was that a reduction in AT1 activation by reducing ANG II levels or by blocking AT1 receptors reduced the renal vasoconstrictor effect of adenosine (14, 17). The same effect was seen when plasma renin and presumably ANG II levels were changed by alterations in dietary Na intake, suggesting that both acute and chronic reductions in AT1 receptor o...

A1adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis

“…In addition, A 1 knockout mice have equivalent mRNA and protein expression of other AR subtypes compared with A 1 wild-type mice. For example, our studies show that A 1 knockout mice express 102, 110, and 100% of A 2a, A2b, and A3 AR mRNA expression of A1 wild-type mice, respectively (n ϭ 2 experiments), confirming the published data of Hansen et al (16).…”

“…The A 1 knockout mice have been shown to have equivalent renal blood flow and glomerular filtration rate compared with A 1 wild-type mice (16). In addition, A 1 knockout mice have equivalent mRNA and protein expression of other AR subtypes compared with A 1 wild-type mice.…”

Renal Phenotype of UT-A Urea Transporter Knockout Mice

“…Measurements of renal blood flow (RBF) were performed in male UT-A1/3 Ϫ/Ϫ mice as described previously (9). After baseline measurements, the response of RBF to intravenous bolus injections of l-NAME (1 g/g body weight [BW]) was assessed.…”

Regulation of Renal Hemodyamics by Purinergic Receptors in Angiotensin II -Induced Hypertension

“…Several conditions that induce the elevation of Ang II concentrations also enhance the vasoconstrictor response of the kidney to adenosine Hansen et al, 2003;Weihprecht et al, 1994;Nishiyama et al, 2001). Furthermore, various studies suggest that Ang II-induced ischemia results in the novo formation of adenosine.…”

“…Nevertheless, the mechanisms involved in such synergic interaction have not been completely elucidated; several studies suggest that under acute changes in the concentration of the corresponding agonists, the degree of activation of Ang II AT1 or adenosine A1 receptors determines the magnitude of the constrictor response of the renal vasculature (Weihprecht et al, 1994). Furthermore, the synergism seems partially mediated by A1 receptors, since in the adenosine A1 knockout mice AT1 and A2a receptors remained unchanged, but the vascular response to Ang II in the kidney was diminished (Hansen et al, 2003). Taking into account that the local renal adenosine concentrations could be the factor that contributes to the interaction with Ang II (Franco et al, 2008), we measured de interstitial adenosine concentrations in the cortex of sham-control and Ang II-treated rats.…”