The discovery of ANP was rapidly followed by a rapid advancement of research on both basic and clinical aspects of NPs and their receptor system. Thus far, three related NPs and three distinct receptors have been identified and cloned that have advanced our knowledge toward understanding the control of high blood pressure, hypertension, and cardiovascular disorders to a great extent. Biochemical and molecular studies have been advanced to examine receptor function and signaling mechanisms and the role of second messenger cGMP in physiology and pathophysiology of hypertension, renal hemo-dynamics, and cardiovascular functions. Tools have been developed to examine receptor internalization, downregulation and/or desensitization of both GC-coupled and GC-uncoupled NP receptors in different cell systems. The development of gene-knockout and gene-duplication mouse models along with transgenic mice have provided a framework for understanding both the physiological and pathophysiological importance of NPs and their receptors and the signaling pathways involved in their mechanisms of action in hypertension and cardiovascular disease states. Although a considerable progress has been made, the transmembrane signal transduction mechanisms of NPs and their receptors remain unresolved. Future challenges should include the identification and characterization of cellular targets of NPs and second messenger cGMP including cytosolic and nuclear proteins, role in gene transcription, cell growth and proliferation, apoptosis, and differentiation. A more vigorous study of the crosstalk with other signaling mechanisms needs to be pursued systematically. Now, NPs are considered as circulating markers of CHF, however, their therapeutic potential for the treatment of cardiovascular diseases such as hypertension, renal insufficiency, cardiac hypertrophy, CHF, and stroke is still lacking. Indeed, the alternative avenues of investigations need to be undertaken, as we are at the initial stage of the molecular therapeutic and pharmacogenomic implications.
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