f-channel nucleotide modulation was investigated in sino-atrial (SA) node cells isolated from rabbit hearts, using an inside-out macropatch configuration. Saturating doses (30 microM) of phosphorothioate derivatives of cAMP, Sp-cAMPS and Rp-cAMPS, were tested on the cAMP-induced shift of I(f) activation. Responses were not altered when Sp-cAMPS was combined with cAMP. When Rp-cAMPS was superfused with subsaturating cAMP concentrations (1-10 microM), it inhibited cAMP-induced I(f) activation shift. cGMP and cIMP reversibly shifted the I(f) conductance-voltage curve to more positive values; however they had a lesser specificity than that of cAMP. The efficacy ranking for I(f) activation by cyclic nucleotides was: cAMP > cGMP > cIMP. Non cyclic nucleotides (ATP, ADP and AMP) failed to change I(f) activation, indicating that the cyclic nature of nucleotides seems to be essential to f-channel modulation. Similarities between f-channels and cyclic nucleotide-gated (CNG) channels are discussed.