We have compared renal A₁ adenosine receptor (AR) regulations in rats after chronic agonist and antagonist treatments. In one group, R-phenylisopropyladenosine (R-PIA), a selective A₁ AR agonist, was infused subcutaneously for 7 days. Another group was fed theophylline, a non-selective AR antagonist, for 2 weeks. Renal cortex membrane A₁ AR binding with 1,3-[³H]-dipropyl-8-cyclopentylxanthine demonstrated ∼40% reduction in the B_max for the R-PIA group without any changes in the K_d values. Neither the B_max nor the K_d changed following chronic theophylline treatment. Renal cortex G_iα-proteins from the R-PIA treated rats decreased by ∼30%. Renal G_iα levels did not change in theophylline-treated rats. Consistent with the A₁ AR desensitization, R-PIA-treated rats had significantly higher basal renin release and showed attenuated A₁ AR-mediated inhibition of renin release. These data suggest that prolonged A₁ AR stimulation results in downregulation of renal A₁ ARs and G_iα, accompanied by desensitization of A₁ AR-mediated inhibitory effects on renin release. Unlike cardiac and brain A₁ ARs, renal A₁ receptors are not subject to up-regulation following chronic antagonist treatment.