Modulating the NO generating system from a medicinal chemistry perspective: current trends and therapeutic options in cardiovascular disease.
An impaired nitric oxide (NO) bioavailability is well-recognized in the pathology of endothelial dysfunction or atherosclerosis, respectively, and characterized by a reduced NO biosynthesis, an accelerated inactivation and/or a decreased sensitivity to NO. Therefore, attempts to increase endogenous NO concentrations or to improve responses to NO stimulation have attracted great pharmaceutical interest for the treatment of several cardiovascular diseases. The biological system of the NO/cGMP cascade is very complex and highly regulated through diverse upstream and downstream molecular and cellular elements and feedback mechanisms. This review summarizes the current options to modulate NO bioavailability for the treatment of cardiovascular disease, with a special focus on targets upstream of cGMP. We also point at the many shortcomings that are associated with the established therapy with nitrates, thereby raising general questions regarding this pharmacological approach. In fact, it is highly desirable to more selectively affect the respective pathologically altered processes in endothelial dysfunction, which ensures a safer and more effective therapy. Approaches to modulate those enzymes that predominate in the regulation of endogenous NO levels represent promising means to achieve this goal: nitric oxide synthases, arginases and dimethylarginine dimethylaminohydrolase. The herein presented novel developments essentially imply a paradigm shift from purely symptomatic to more causative therapeutics which opens up opportunities to not only treat ischemic heart disease but many more cardiovascular diseases.
Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76-78, D-24118 Kiel, Germany. dschade@pharmazie.uni-kiel.de
Dennis
D
Schade
Jürke
J
Kotthaus
Bernd
B
Clement
D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000628:therapy*; D002626:Chemistry, Pharmaceutical / Q000379:methods / Q000639:trends*; D006801:Humans; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology; D016896:Treatment Outcome
D020030:Nitric Oxide Donors; D009569:Nitric Oxide