Autocrine and paracrine actions of natriuretic peptides in the heart.

The natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), are a family of polypeptide mediators exerting numerous actions in cardiovascular homeostasis. ANP and BNP are cardiac derived, being secreted and up-regulated in myocardium in response to many pathophysiological stimuli. CNP is an endothelium-derived mediator. The classical endocrine effects of ANP and BNP on fluid homeostasis and blood pressure, especially in conditions characterised by left ventricular dysfunction, are well recognised and extensively researched. However, there is accumulating evidence that, in addition to endocrine actions, ANP and BNP exhibit important autocrine and paracrine functions within the heart and coronary circulation. These include regulation of myocyte growth, inhibition of fibroblast proliferation and extracellular matrix deposition, a cytoprotective anti-ischaemic (preconditioning-like) function, and influences on coronary endothelium and vascular smooth muscle proliferation and contractility. Most if not all of these actions can be ascribed to particulate guanylyl cyclase activation because the ANP/BNP receptor, natriuretic peptide receptor (NPR)-A, has an intracellular guanylyl cyclase domain. Subsequent elevation of the intracellular second messenger cGMP may exert diverse physiological effects through activation of cGMP-dependent protein kinases (cGK), predominantly cGK-I. However, there appear to be other contributory mechanisms in several of these actions, including the augmentation of nitric oxide synthesis. These diverse actions may represent counterregulatory mechanisms in the pathophysiology of many cardiovascular diseases, not just those typified by left ventricular dysfunction. Ultimately, insights from the autocrine/paracrine actions of natriuretic peptides may provide routes to therapeutic application in cardiac diseases of natriuretic peptides and drugs that modify their availability.