Atrial natriuretic peptide (ANP) relaxes the vascular smooth muscle via particulate guanylate cyclase. Smooth muscle cells isolated from the caecal circular muscle layer of the guinea pig were used to examine the direct inhibitory effect of ANP on those cells. The role of adenylate cyclase, particulate guanylate cyclase, and soluble guanylate cyclase in the direct inhibitory effect of ANP on contraction of this muscle cell induced by carbachol was investigated. ANP inhibited the contractile response produced by 10(6)M carbachol in a concentration-dependent manner, with an IC50 value of 8nM. An inhibitor of adenylate cyclase (2',5'-dideoxyadenosine) and two inhibitors of particulate guanylate cyclase (HS-142-1, and PMA) had no significant effect on the relaxation produced by ANP. In contrast, an inhibitor of soluble guanylate cyclase (LY83583) significantly and completely inhibited the relaxation produced by ANP. This is the first report demonstrating the direct inhibitory action of ANP on the isolated caecal smooth muscle cells via soluble guanylate cyclase, which differs from the intracellular mechanism responsible for the relaxation of vascular smooth muscle produced by ANP.