Protein kinase G (PKG) is a major downstream effector of the nitric oxide (NO) and natriuretic peptide (NP) signalling pathways, each being linked to a respective guanylate cyclase (soluble-sGC, particulate-pGC) to generate cyclic guanosine 3’5’ monophosphate (cGMP), thereby activating the kinase. Levels of cGMP and thus PKG activation are also regulated by a select group of phosphodiesterases (PDEs) that control cGMP hydrolysis. In vessels, PKG1 induces smooth muscle relaxation in response to nitric oxide signalling and thus lowers systemic and pulmonary blood pressure. In platelets, PKG1 stimulation by cGMP inhibits activation and aggregation, and in experimental models of heart failure (HF), PKG1 activation by inhibiting cGMP degradation is protective. The net effect of the above-mentioned signalling is cardiovascular protection.[1]