Novel therapies for cyclic GMP control of vascular smooth muscle growth.
Cyclic GMP, guanosine 3',5'-cyclic monophosphate, is a critical and multifunctional second-messenger molecule that mediates diverse physiological and pathophysiological functions in cardiac and vascular tissues. Synthesized through nitric oxide, carbon monoxide, and/or natriuretic peptide-mediated guanylate cyclase stimulation and guanosine triphosphate dephosphorylation, cyclic GMP is capable of stimulating a cascade of serine/threonine kinase events, including signaling through cyclic GMP- and/or cyclic AMP-dependent protein kinases, eliciting protein kinase-independent actions such as modulation of ion channels or transporters, or undergoing hydrolytic degradation through actions of cyclic GMP-regulated phosphodiesterases. Substrates, enzymes, cofactors, and associated variables in this multifaceted system have historically been targets of vital pharmacotherapies with perhaps most common the use of vascular smooth muscle-targeting organonitrates in cardiac patients and phosphodiesterase inhibitors in individuals with erectile dysfunction. Accumulating basic science and clinical evidence, however, suggests that cyclic GMP signaling is compromised under conditions of disease or elevated physiological stresses. Moreover, nitric oxide can stimulate an array of cytotoxic effects and nitric oxide-based therapies can be limited by diminished bioactivity and the development of tachyphylaxis or tolerance after prolonged use. Consequently, an emerging area for clinical drug development and therapeutic drug evaluation for conditions of cardiovascular adversity has focused on identification of cyclic GMP signaling pathways that act under oxidized or nitric oxide-unresponsive conditions and/or that operate irrespective of nitric oxide-induced complications. The aim of this therapeutic review is to describe novel, nitric oxide-alternate avenues for cyclic GMP signaling in vascular smooth muscle growth with particular emphasis on pharmacotherapeutics of recently characterized cyclic GMP-specific approaches.
Tulis
David A
DA
Cardiovascular Disease Research Program, J. L. Chambers Biomedical/Biotechnology Research Institute & Department of Biology, North Carolina Central University, Durham, North Carolina, USA. dtulis@nccu.edu
D000818:Animals; D002248:Carbon Monoxide / Q000502:physiology; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000188:drug therapy / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D006152:Cyclic GMP / Q000502:physiology*; D020536:Enzyme Activators / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D020536:Enzyme Activators; D007191:Indazoles; D011720:Pyrazoles; D011725:Pyridines; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009569:Nitric Oxide; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D006162:Guanylate Cyclase; D006152:Cyclic GMP