Requirement of intact adenosine a1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine

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)R-/-) and littermate wild-type (A(1)R+/+) 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)R+/+ but not in A(1)R-/- 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)R-/- 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.