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Activation of nitric oxide (NO)‐insensitive soluble guanylate cyclase does not provide greater benefit than NO‐sensitive stimulation in acute and chronic models of cardiovascular disease associated with oxidative stress
Author(s) -
Costell Melissa H.,
Bernard Roberta E.,
Alsaid Hasan,
Upson John J.,
Olzinski Alan R.,
Morgan Lisa A.,
Grondin Pascal O.,
Ancellin Nicolas,
Dodic Nerina,
Gellibert Francoise,
Jucker Beat M.,
Jolivette Larry J.,
Willette Robert N.,
Schnackenberg Christine G.,
Behm David J.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.643.5
Soluble guanylate cyclase (sGC), the primary mediator of nitric oxide (NO), exists as reduced (NO‐sensitive) and oxidized (NO‐insensitive) forms. Because NO‐insensitive sGC is the dominant form under conditions of oxidative stress, we tested the hypothesis that activation of NO‐insensitive sGC improves cardiovascular function more than NO‐sensitive sGC stimulation during acute and chronic oxidative stress. In acute coronary artery ischemia/reperfusion in Sprague Dawley rats, the NO‐insensitive sGC activator GSK2181236A (0.1, 1 mg/kg, p.o.) or the NO‐sensitive sGC stimulator BAY60‐4552 (0.3, 3 mg/kg, p.o.) had no effect on infarct size, area at risk, left ventricle hemodynamics or mortality at 24 hours after reperfusion. In stroke‐prone SHR with high salt/high fat intake, 7 weeks of treatment with GSK2181236A (1 mg/kg, p.o.) or BAY60‐4552 (0.3 mg/kg, p.o.) mildly reduced mean arterial pressure (5–10 mmHg) and decreased cardiac mRNA expression of ANF and alpha skeletal actin, microalbuminuria, and mortality, but had no effect on cardiac remodeling or function, or endothelium‐dependent vasorelaxation. These studies suggest that activation of NO‐insensitive sGC does not provide any clear advantage over NO‐sensitive sGC stimulation in cardiovascular disease associated with oxidative stress.