We have previously shown that ANP causes differential constriction of the splenic vasculature of the rat (veins greater than arteries), which may be inhibited by blocking the production of cGMP with A7195. In this paper, we report experiments done on vessels derived from GC-A knockout mice. Small splenic arteries (~150µm diameter) and veins (~250µm diameter) were dissected from male GC-A deficient 129sv mice or age-matched wild type controls, and mounted in a wire myograph.. In the wild-type mice, ANP exhibited higher potency in the veins than in the arteries (EC₅₀ values wild-type mice: artery, 8 ± 3 x 10^-9M, n=5 versus vein, 6 ± 4 x 10^-10M, n=5; p<0.05). The concentration-response curve for ANP-induced vasoconstriction was also shifted leftward in denuded compared with intact arteries (EC₅₀ values: denuded artery: 5 ± 3 x 10^-10M, n=5 versus intact artery, 8 ± 3 x 10^-9M, n=5; p<0.05) i.e. the denuded vessels were more reactive. By contrast, ANP caused no significant change in tension from baseline in intact splenic arteries, intact splenic veins or denuded splenic arteries derived from the GC-A deficient mice, although these vessels did show normal concentration-dependent increases in tension to phenylephrine. We conclude that ANP causes vasoconstriction in the splenic vasculature by an endothelium-independent mechanism, mediated via guanylyl cyclase.