Central Effects of Caffeine on Renal Renin Secretion and Norepinephrine Spillover

Abstract

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.

Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF1Rats

“…[35] The present study and our recent work [13,33,36] are suggestive of increased renin activity in caffeine-treated animals.…”

Regulation of Renal A₁ Adenosine Receptors in vivo

“…Adenosine, via acting on specific cell surface receptors, either inhibits (via A 1 AR and G i ) or stimulates (via A 2a AR and G s ) renin release from the kidney [5, 9]. Although the kidney possesses both A 1 and A 2a ARs, endogenous renal adenosine has been shown to tonically inhibit basal renin release via the A 1 AR and G i -mediated pathway [8, 33]. The A 1 AR activation increases the intracellular calcium and inhibits the cAMP pathway of the renin secreting granular cell, leading to reduced release of renin.…”

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

“…NE was quantified using high-performance liquid chromatography with electrochemical detection as previously described by us (58).…”