ABSTRACT Purpose The induction of penile erection depends on the depletion of free intracellular Ca 2+ from the cytosol into the sarcoplasmic reticulum of smooth muscle cells of the corpus cavernosum. This process is regulated by a complex system of signal transduction pathways. In this context guanylyl and adenylyl cyclases as well as cyclic nucleotide monophosphate degrading phosphodiesterases have essential roles and represent important target molecules for the development of drugs for erectile dysfunction. Sildenafil, which is an inhibitor of phosphodiesterase 5, is frequently used for this application but, unfortunately, it has undesirable side effects. Therefore, we investigated the suitability of membrane bound guanylyl cyclases as alternative target proteins. Materials and Methods We determined mRNA transcripts specific for guanylyl cyclase B, a receptor of the peptide hormone C-type natriuretic polypeptide, in human corpus cavernosum. We performed immunohistochemistry to evaluate the presence of guanylyl cyclase B in corpus cavernosum and helical artery smooth muscle cells. We further investigated whether C-type natriuretic polypeptide increases intracellular cyclic guanosine monophosphate and performed organ bath studies using corpus cavernosum muscle strips and C-type natriuretic polypeptide at concentrations of 1 to 1 μM. Results mRNA transcripts were detected encoding for guanylyl cyclase-B, a receptor of the peptide hormone C-type natriuretic polypeptide, in human corpus cavernosum. This finding was verified at the protein level by immunohistochemistry that demonstrated guanylyl cyclase B in corpus cavernosum and helical artery smooth muscle cells. We further noted that C-type natriuretic polypeptide increased intracellular cyclic guanosine monophosphate. In organ bath studies with corpus cavernosum muscle strips C-type natriuretic polypeptide at concentrations of 1 to 1 μM. led to smooth muscle relaxation from 5% to 40%. Conclusions The results indicate a role for C-type natriuretic polypeptide and its receptor in the induction of penile erection and its possible future therapeutic use for erectile dysfunction.