The effect of adenosine on responses to sympathetic nerve stimulation was studied in the isolated perfused rat kidney. Adenosine at 1, 3 and 10 micrograms/ml caused significant impairment of renal sympathetic neurotransmission as evidenced in a dose-dependent reduction in the vasoconstrictor responses elicited by periarterial nerve stimulation at 2, 4 and 8 Hz. Vasoconstriction to exogenous norepinephrine was unaffected by adenosine except at 10 micrograms/ml where there was a slight reduction in response to norepinephrine. Theophylline, an adenosine receptor antagonist, inhibited the above action of adenosine at the frequencies of 2 and 4 Hz. At 2 Hz, 10 microM theophylline completely blocked the effect of 1 and 3 micrograms/ml adenosine and reduced by 50% the inhibitory action of 10 micrograms/ml. Higher concentration of theophylline (50 microM) was required to antagonize the action of adenosine at 4 Hz. These results indicate that adenosine can inhibit sympathetic neurotransmission in the rat kidney through a presynaptic purinergic mechanism. The physiological and pharmacological significance of this presynaptic action of adenosine is discussed.