1. Second messenger responses to natriuretic peptides were studied in guinea-pig cerebellar slices by use of radioactive precursors. 2. The rank order of potency of the different natriuretic peptides in generating [3H]-guanosine 3':5'-cyclic monophosphate (cyclic GMP) was atrial natriuretic peptide (ANP) > brain natriuretic peptide (BNP) >> C-type natriuretic peptide (CNP) with EC50 values of 19.5 +/- 8.8 nM for ANP and 169 +/- 41 nM for BNP. CNP induced [3H]-cyclic GMP accumulation only at concentrations greater than 1 microM. 3. An additive response to ANP (1 microM) was observed in the presence of the adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA, 10 microM) or the soluble guanylyl cyclase activator, sodium nitroprusside (SNP, 100 microM) for [3H]-cyclic GMP accumulation. 4. ANP, BNP and CNP (all at 1 microM) failed to alter significantly either basal-, forskolin- (10 microM), isoprenaline- (100 microM), or NECA- (10 microM) induced [3H]-cyclic AMP generation. Natriuretic peptides also did not change the [3H]-cyclic AMP steady-state reached after 10 min of treatment with 10 microM forskolin. 5. Natriuretic peptides failed to elicit significant accumulation of [3H]-inositol phosphates at concentrations up to 10 microM. 6. These data are consistent with the presence of ANPA, rather than ANPB or clearance receptors (C-receptors), linked to second messenger cascades in guinea-pig cerebellar slices.