TY - JOUR
T1 - Heme-dependent and independent soluble guanylate cyclase activators and vasodilation
AU - Priviero, Fernanda B.M.
AU - Webb, R. Clinton
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2010/9
Y1 - 2010/9
N2 - Since the discovery of nitric oxide (NO), which is released from endothelial cells as the main mediator of vasodilation, its target, the soluble guanylyl cyclase (sGC), has become a focus of interest for the treatment of diseases associated with endothelial dysfunction. NO donors were developed to suppress NO deficiency; however, tolerance to organic nitrates was reported. Non-NO-based drugs targeting sGC were developed to overcome the problem of tolerance. In this review, we briefly describe the process of sGC activation by its main physiological activator NO and the advances in the development of drugs capable of activating sGC in a NO-independent manner. sGC stimulators, as some of these drugs are called, require the integrity of the reduced heme moiety of the prosthetic group within the sGC and therefore are called heme-dependent stimulators. Other drugs are able to activate sGC independent of heme moiety and are hence called heme-independent activators. Because pathologic conditions modulate sGC and oxidize the heme moiety, the heme-independent sGC activators could potentially become drugs of choice because of their higher affinity to the oxidized enzyme. However, these drugs are still undergoing clinical trials and are not available for clinical use.
AB - Since the discovery of nitric oxide (NO), which is released from endothelial cells as the main mediator of vasodilation, its target, the soluble guanylyl cyclase (sGC), has become a focus of interest for the treatment of diseases associated with endothelial dysfunction. NO donors were developed to suppress NO deficiency; however, tolerance to organic nitrates was reported. Non-NO-based drugs targeting sGC were developed to overcome the problem of tolerance. In this review, we briefly describe the process of sGC activation by its main physiological activator NO and the advances in the development of drugs capable of activating sGC in a NO-independent manner. sGC stimulators, as some of these drugs are called, require the integrity of the reduced heme moiety of the prosthetic group within the sGC and therefore are called heme-dependent stimulators. Other drugs are able to activate sGC independent of heme moiety and are hence called heme-independent activators. Because pathologic conditions modulate sGC and oxidize the heme moiety, the heme-independent sGC activators could potentially become drugs of choice because of their higher affinity to the oxidized enzyme. However, these drugs are still undergoing clinical trials and are not available for clinical use.
KW - endothelial dysfunction
KW - nitric oxide
KW - soluble guanylyl cyclase activators
KW - vascular disease
KW - vascular smooth muscle
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UR - http://www.scopus.com/inward/citedby.url?scp=77957562992&partnerID=8YFLogxK
U2 - 10.1097/FJC.0b013e3181eb4e75
DO - 10.1097/FJC.0b013e3181eb4e75
M3 - Review article
C2 - 20571429
AN - SCOPUS:77957562992
SN - 0160-2446
VL - 56
SP - 229
EP - 233
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
IS - 3
ER -