In hypertensive TGR(mREN2)27 rats (TGR), the subsensitivity of vascular guanylyl cyclase to nitric oxide could depend on oxidized heme, reduced heme content, or decreased expression of the enzyme. In this study, enzyme activity was stimulated by protoporphyrin-IX, which acts independently of heme, and expression was assessed by Western blot analysis. In TGR aorta, maximum stimulation of soluble guanylyl cyclase by protoporphyrin-IX was 40% lower than in Sprague–Dawley controls, and expression of the β1-subunit of the enzyme was reduced by 50% (P<0.05, t-test). In conclusion, decreased expression of soluble guanylyl cyclase leads to a blunted response of the nitric oxide–cGMP (guanosine 3′,5′-cyclic monophosphate) pathway in TGR aorta.