Requirement of Intact Adenosine A₁Receptors for the Diuretic and Natriuretic Action of the Methylxanthines Theophylline and Caffeine

Abstract

Although the diuretic and natriuretic effects of the methylxanthines caffeine and theophylline are well established, the mechanisms responsible for these effects are unclear and may be related to inhibition of phosphodiesterases and/or antagonism of adenosine receptors. With regard to the latter, pharmacological blockade of A 1 receptors can induce diuresis and natriuresis by inhibition of proximal tubular reabsorption. To elucidate the role of the A 1 receptor in renal actions of methylxanthines, experiments were performed in A 1 receptor knockout (A 1 RϪ/Ϫ) and littermate wild-type (A 1 Rϩ/ϩ) mice. Urinary excretion was determined in awake mice in metabolic cages over 3 h in response to theophylline (as theophylline 2 / ethylenediamine, 45 mg/kg), caffeine (45 mg/kg), or vehicle (0.9 ml/30 g b.wt. of 0.85% NaCl) given by oral gavage. Theophylline and caffeine elicited a diuresis and natriuresis (in absolute terms and related to urinary creatinine excretion) in A 1 Rϩ/ϩ but not in A 1 RϪ/Ϫ mice. In a second series, the renal effect of intravenous application of theophylline (30 mg/kg) was determined in clearance experiments under anesthesia. This study revealed that the blunted diuretic and natriuretic effect of theophylline in A 1 RϪ/Ϫ mice was not due to different responses in blood pressure or glomerular filtration rate. The data indicate that an intact A 1 receptor is necessary for caffeine-and theophylline-induced inhibition of renal reabsorption causing diuresis and natriuresis. This is consistent with the assumption that A 1 receptor blockade mediates these effects.Caffeine and theophylline are members of the methylxanthine family that are very widely consumed and exert well described behavioral effects. In the kidney, methylxanthines induce diuresis and natriuresis, an effect first described by Davis and Shock (1949). The mechanisms by which methylxanthines act as diuretics and natriuretics are not completely understood. Since methylxanthines are nonselective adenosine receptor antagonists (Fredholm et al., 2001), it is conceivable that the changes in urine excretion are the result of inhibition of the renal actions of endogenous adenosine.

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

“…Mice were randomized to application of EX4 (10 g/kg ip; Sigma-Aldrich, St. Louis, MO), ALG (10 mg/kg ip; Takeda Pharmaceuticals, Oak Grove, IL), or vehicle (0.85% NaCl, 2 l/g body wt ip). After their bladders were emptied, the mice were NaCl-loaded by oral gavage (0.85% NaCl, 30 l/g body wt, ϳ30% of daily NaCl intake) and placed in metabolic cages for quantitative urine collection over 3 h without access to food or water (32,33); then blood glucose was measured by tail snip.…”

“…Mice were anesthetized with thiobutabarbital (100 mg/kg ip, 2 l/g body wt; Sigma-Aldrich, St. Louis, MO) and ketamine (100 mg/kg im, 2 l/g body wt; Butler, Dublin, OH) and prepared for renal clearance experiments, as described elsewhere (31,32). The jugular vein was cannulated for continuous infusion of 2.25% bovine serum albumin in 0.85% NaCl at 0.4 ml·h Ϫ1 ·30 g body wt Ϫ1 .…”

Mécanismes de l’effet diurétique de la caféine

“…Ces études ont mis en évidence le rôle crucial du récepteur A1. En effet, l'administration de caféine n'a pas d'effet diurétique chez les souris défi cientes en récepteur A1R alors qu'elle provoque bien une augmentation du débit urinaire et de la natriurèse (voir ci après) chez la souris sauvage [20]. Un des méca nismes proposés pour expliquer l'effet diurétique de la caféine est le blocage du rétrocontrôle tubulo gloméru laire exercé par l'adénosine via ce récepteur A1.…”

“…Outre cet effet natriurétique, il existe d'autres arguments en faveur d'une diurèse tubulaire proximale induite par la caféine. Sous caféine, on observe notamment un accroissement de la calciurie de débit (mesurée en mmol/kg/jour) [20]. Cette perte calcique a des consé quences sur l'homéostasie minérale, avec une élévation des taux de parathormone (PTH) chez les grands consommateurs de café dont les apports calciques sont faibles [25,26].…”

Modulation of adenosine receptor expression in the proximal tubule: a novel adaptive mechanism to regulate renal salt and water metabolism

“…Thus both acute nonspecific adenosine receptor antagonism and specific blockade of A1-AR both result in increased natriuresis and diuresis, in part due to reduced proximal tubular reabsorption (2,3,5,24). Consistent with the antinatriuretic and antidiuretic effects of adenosine being mediated by A1-AR, nonspecific adenosine receptor antagonists like theophylline and caffeine induce natriuresis and diuresis in wild-type mice but have no effect on renal salt and water excretion in A1-AR-deficient mice (20). What, then, is the effect of a cup of coffee on natriuresis and diuresis in humans?…”