C-type natriuretic peptide (CNP) represents a key paracrine member of the natriuretic peptide family that play an important role in the regulation of vascular tone and local blood flow. CNP is found abundantly in vascular endothelial cells and it is now clear that CNP can be released from the endothelium to act on adjacent cells, both in the vessel wall and the circulation. Thus, it has been shown that CNP hyperpolarises and dilates vascular smooth muscle in the mammalian resistance vasculature, inhibits leukocyte recruitment and platelet-leukocytes interactions, reduces vascular smooth muscle proliferation, promotes endothelial cell growth and protects against myocardial ischaemia-reperfusion injury.
Our previous work has demonstrated that CNP acts as an endothelium-derived hyperpolarising factor (EDHF) in the rat mesenteric and coronary vascular beds. Moreover, we have provided evidence that this activity is dependent on activation of a new vascular signalling pathway involving natriuretic peptide receptor-C (NPR-C) and G protein-gated inwardly rectifying K+ channels (GIRKs). Indeed, using a novel selective NPR-C antagonist, M372049, we have shown that NPR-C activation has a positive signalling role that underlies several aspects of cardiovascular homeostasis (in addition to its classical role as a clearance receptor to bind and remove natriuretic peptides from the circulation); these newly identified pathways include vascular smooth muscle hyperpolarisation, inhibition of leukocyte trafficking and reductions in platelet reactivity. M372049 has also proven an invaluable tool to elucidate the significance of EDHF in regulating resistance artery tone; by combining classical inhibitors of EDHF with M372049 we have delineated two distinct pathways in mediating the bioactivity of EDHF, intimating the existence of at least two EDHFs. Moreover, one of these systems is reliant on NPR-C activation.
In sum, the importance of CNP/NPR-C signalling in the vasculature is now emerging and it is likely to exert a key cytoprotective, anti-atherogenic effect on the blood vessel wall. In addition, CNP acts as an EDHF in some vascular beds and therefore contributes to the regulation of vascular tone and blood pressure. Agents mimicking the bioactivity of CNP, via NPR-C activation, are likely to represent novel therapies for cardiovascular disease.