Recent studies demonstrated that the influence of the macula densa on glomerular filtration is abolished in adenosine A(1) receptor (A(1)AR) knockout mice. Inasmuch as the macula densa not only regulates glomerular filtration but also controls the activity of the renin system, the present study aimed to determine the role of the A(1)AR in macula densa control of renin synthesis and secretion. Although a high-salt diet over 1 wk suppressed renin mRNA expression and renal renin content to similar degrees in A(1)AR(+/+), A(1)AR(+/-), and A(1)AR(-/-) mice, stimulation of Ren-1 mRNA expression and renal renin content by salt restriction was markedly enhanced in A(1)AR(-/-) compared with wild-type mice. Pharmacological blockade of macula densa salt transport with loop diuretics stimulated renin expression in vivo (treatment with furosemide at 1.2 mg/day for 6 days) and renin secretion in isolated perfused mouse kidneys (treatment with 100 microM bumetanide) in all three genotypes to the same extent. Taken together, our data are consistent with the concept of a tonic inhibitory role of the A(1)AR in the renin system, whereas they indicate that the A(1)AR is not indispensable in macula densa control of the renin system.