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Evidence is mounting that NO plays a role in the cardiovascular and renal adaptation to the hemorrhagic shock secondary to major blood loss. Recently, we reported cardiac and renal NO-dependent protective mechanisms activated by the hypovolemic state that include stimulation of NO synthase (NOS) expression and activity. In the heart, an increase in endothelial NOS is an early response to regulate cardiac function after blood loss. Meanwhile, inducible NOS increases heart dysfunction in later stages of sustained hemorrhagic shock. Additionally, the hypovolemic state induced changes in water homeostasis associated with alterations in inner medullary aquaporin water channel type 2 (AQP2) protein expressions and subcellular localization. NO production is one of the causes of the age-associated response that modulates AQP2 expression/trafficking in the inner collecting duct principal cells in response to hemorrhage. The complex regulation of NOS in cardiovascular and renal physiology depends on the magnitude of hemorrhage and age. The adaptive enhancement of NO synthesis and availability activates or increases expression of other protective factors, including heat shock proteins, antioxidants and prostaglandins, making the protection more robust and sustained. The work with laboratory animals and experimental hemorrhagic shock identified mitochondria as a sensitive subcellular compartment involved in the NO-mediated response to hypovolemic state. In a separate line of research, mtNOS was probed as a likely pacemaker of mammalian aging. Finally, further research based on the participation of mtNOS and the relationships between NO and other modulators of heart and kidney function, as well as the impact of aging in tissue adaptation to hypovolemia, are new research lines and hypothetical therapeutic strategies for the prevention and early treatment of tissue dysfunction.
Current Enzyme Inhibition aims to publish all the latest and outstanding developments in enzyme inhibition studies with regards to the mechanisms of inhibitory processes of enzymes, recognition of active sites, and the discovery of agonists and antagonists, leading to the design and development of new drugs of significant therapeutic value. Each issue contains a series of timely, in-depth reviews written by leaders in the field, covering a range of enzymes that can be exploited for drug development. Current Enzyme Inhibition is an essential journal for every pharmaceutical and medicinal chemist who wishes to have up-to-date knowledge about each and every development in the study of enzyme inhibition.