Guanosine 3′5′ cyclic monophosphate (cGMP) is synthesized by soluble guanylyl cyclase (sGC) when vascular smooth muscle is stimulated with nitric oxide (NO) and nitrovasodilators and by particulate guanylate cyclases (pGC) when stimulated with natriuretic peptides. The intracellular cGMP levels are determined by the balance of the synthesis of this cyclic nucleotide by sGC and pGC and its hydrolysis mainly by the type 5 phosphodiesterase. cGMP exerts its action predominantly through the activation of cGMP-dependent protein kinase (PKG) resulting in reduced cytosolic Ca2+ and decreased Ca2+ sensitivity of the myofilaments and consequently vasodilatation. In these processes the activation of the large-conductance Ca2+-activated K+ channel, phosphorylation of IP3R-associated cGMP kinase substrate, phosphorylation of myosin phosphatase target subunit 1, and counteraction on Rho A/Rho kinase activity may serve as the major mechanisms for the cGMP/PKG signaling.