1. The present study examined the effect of exogenous atrial natriuretric peptide (ANP), alone or in presence of inhibitors of the two major mechanisms for clearing ANP, metabolism by neutral endopeptidase-24.11 (NEP) and internalization by C-ANP receptors, on arteriolar responses using intravital microscopy on the rat cremaster muscle after intravenous or topical administration of the peptide. 2. Topical application of ANP (3 x 10(-10) to 3 x 10(-8) M) produced a gradual increase in arteriolar diameter. NEP inhibitors, thiorphan (30 mg kg-1, i.v.), kelatorphan (10 mg kg-1, i.v.) and retrothiorphan (25 mg kg-1, i.v.) alone, did not significantly affect vascular tone but caused significant potentiation of the arteriolar responses to topically applied ANP. 3. When given as an i.v. bolus, ANP dilates skeletal arterioles at a high dose (20 micrograms kg-1). At a lower dose (10 micrograms kg-2), ANP alone or with retrothiorphan or the C-ANP receptor ligand C-ANP (4-23) did not produce any arteriolar responses, while after the combined administration of the two inhibitors, an increase in arteriolar diameter was induced. 4. These results indicate that low doses of topically applied ANP dilate rat cremaster arterioles and that the vasodilator responses can be potentiated by NEP inhibition. When given as an i.v. bolus, a high dose of ANP can also dilate skeletal arterioles. However at a lower dose the rapid metabolism of the peptide prevents it from producing its action.