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      Regulation of Renal A 1 Adenosine Receptors in vivo

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          We have compared renal A<sub>1</sub> adenosine receptor (AR) regulations in rats after chronic agonist and antagonist treatments. In one group, R-phenylisopropyladenosine (R-PIA), a selective A<sub>1</sub> AR agonist, was infused subcutaneously for 7 days. Another group was fed theophylline, a non-selective AR antagonist, for 2 weeks. Renal cortex membrane A<sub>1</sub> AR binding with 1,3-[<sup>3</sup>H]-dipropyl-8-cyclopentylxanthine demonstrated ∼40% reduction in the B<sub>max </sub> for the R-PIA group without any changes in the K<sub>d</sub> values. Neither the B<sub>max</sub> nor the K<sub>d</sub> changed following chronic theophylline treatment. Renal cortex G<sub>i</sub>α-proteins from the R-PIA treated rats decreased by ∼30%. Renal G<sub>i</sub>α levels did not change in theophylline-treated rats. Consistent with the A<sub>1</sub> AR desensitization, R-PIA-treated rats had significantly higher basal renin release and showed attenuated A<sub>1</sub> AR-mediated inhibition of renin release. These data suggest that prolonged A<sub>1</sub> AR stimulation results in downregulation of renal A<sub>1</sub> ARs and G<sub>i</sub>α, accompanied by desensitization of A<sub>1</sub> AR-mediated inhibitory effects on renin release. Unlike cardiac and brain A<sub>1</sub> ARs, renal A<sub>1</sub> receptors are not subject to up-regulation following chronic antagonist treatment.

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          Central effects of caffeine on renal renin secretion and norepinephrine spillover.

          Endogenous adenosine in the brain may inhibit central sympathetic tone and thereby restrain renin release, a mechanism that may be particularly important when sympathetic activity is enhanced. The purpose of our study was to test the hypothesis that the adenosine receptor antagonist caffeine increases renin release in part by disabling the central nervous system (CNS) adenosine brake on renin release. This hypothesis was tested by conducting three protocols in anesthetized rats. In the first protocol, intracerebroventricular (i.c.v.) infusions of caffeine (10 micrograms/kg/min) did not alter either bradycardic responses to intravenous (i.v.) infusion of N6-cyclopentyladenosine (CPA, A1-receptor agonist) or depressor responses to i.v. infusions of CGS21680 (A1-receptor agonist). However, i.c.v. caffeine did block bradycardic responses to i.c.v. boluses of CPA and depressor responses to i.c.v. boluses of CGS21680, thus demonstrating that i.c.v. caffeine at the dose used blocks CNS but not peripheral adenosine receptors. In the second protocol, hydralazine (1 and 10 mg/kg, administered intraperitoneally) significantly enhanced both the renal secretion of renin and the renal spillover of norepinephrine (NE), thus confirming that hydralazine can increase renin release by unloading arterial baroreceptors and increasing sympathetic tone to the kidneys. In the third protocol, the effects of i.c.v. caffeine (10 micrograms/kg/min) on hydralazine-induced (1 and 10 mg/kg, administered intraperitoneally) changes in renal secretion of renin and renal NE spillover were investigated. In this protocol, i.c.v. caffeine did not alter baseline values for either the renal secretion of renin or NE. In contrast, i.c.v. caffeine significantly (p = 0.03) enhanced the increase in renal renin secretion induced by 1 and 10 mg/kg hydralazine (for 1 mg/kg hydralazine delta of 6.4 +/- 46.7 and 142.4 +/- 142.9 renin activity/min/kg body weight in control and caffeine-treated animals, respectively; for 10 mg/kg hydralazine, delta 227.8 +/- 73.9 and 600.8 +/- 168.9 renin activity/min/kg body weight in control and caffeine-treated animals, respectively). The enhanced renin-secretion response to hydralazine in caffeine-treated rats was accompanied by augmented hydralazine-induced increase in renal NE spillover (p = 0.035). These data strongly support the hypothesis of a CNS adenosine brake on renin release that is disabled by caffeine.
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            Chronic exposure to subcutaneously implanted methylxanthines


              Author and article information

              Nephron Exp Nephrol
              Cardiorenal Medicine
              S. Karger AG
              09 January 2002
              : 10
              : 1
              : 43-50
              aDepartment of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, N.Y., and bDepartment of Physiology, New York Medical College, Valhalla, N.Y., USA
              49897 Exp Nephrol 2002;10:43–50
              © 2002 S. Karger AG, Basel

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              Figures: 6, References: 34, Pages: 8
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