TY - JOUR AU - Costell, Melissa AU - Ancellin, Nicolas AU - Bernard, Roberta AU - Zhao, Shufang AU - Upson, John AU - Morgan, Lisa AU - Hauk, Kristeen AU - Olzinski, Alan AU - Ballard, Victoria AU - Herry, Kenny AU - Grondin, Pascal AU - Dodic, Nerina AU - Mirguet, Olivier AU - Bouillot, Anne AU - Gellibert, Francoise AU - Coatney, Robert AU - Lepore, John AU - Jucker, Beat AU - Jolivette, Larry AU - Willette, Robert AU - Schnackenberg, Christine AU - Behm, David PY - 2012 M3 - Original Research TI - Comparison of Soluble Guanylate Cyclase Stimulators and Activators in Models of Cardiovascular Disease Associated with Oxidative Stress JO - Frontiers in Pharmacology UR - https://www.frontiersin.org/articles/10.3389/fphar.2012.00128 VL - 3 SN - 1663-9812 N2 - Soluble guanylate cyclase (sGC), the primary mediator of nitric oxide (NO) bioactivity, exists as reduced (NO-sensitive) and oxidized (NO-insensitive) forms. We tested the hypothesis that the cardiovascular protective effects of NO-insensitive sGC activation would be potentiated under conditions of oxidative stress compared to those of NO-sensitive sGC stimulation. The cardiovascular effects of the NO-insensitive sGC activator GSK2181236A [a low, non-depressor dose, and a high dose which lowered mean arterial pressure (MAP) by 5–10 mmHg] and those of equi-efficacious doses of the NO-sensitive sGC stimulator BAY 60-4552 were assessed in (1) Sprague Dawley rats during coronary artery ischemia/reperfusion (I/R) and (2) spontaneously hypertensive stroke prone rats (SHR-SP) on a high salt/fat diet (HSFD). In I/R, neither compound reduced infarct size 24 h after reperfusion. In SHR-SP, HSFD increased MAP, urine output, microalbuminuria, and mortality, caused left ventricular hypertrophy with preserved ejection fraction, and impaired endothelium-dependent vasorelaxation. The low dose of BAY 60-4552, but not that of GSK2181236A, decreased urine output, and improved survival. Conversely, the low dose of GSK2181236A, but not that of BAY 60-4552, attenuated the development of cardiac hypertrophy. The high doses of both compounds similarly attenuated cardiac hypertrophy and improved survival. In addition to these effects, the high dose of BAY 60-4552 reduced urine output and microalbuminuria and attenuated the increase in MAP to a greater extent than did GSK2181236A. Neither compound improved endothelium-dependent vasorelaxation. In SHR-SP isolated aorta, the vasodilatory responses to the NO-dependent compounds carbachol and sodium nitroprusside were attenuated by HSFD. In contrast, the vasodilatory responses to both GSK2181236A and BAY 60-4552 were unaltered by HSFD, indicating that reduced NO-bioavailability and not changes in the oxidative state of sGC is responsible for the vascular dysfunction. In summary, GSK2181236A and BAY 60-4552 provide partial benefit against hypertension-induced end-organ damage. The differential beneficial effects observed between these compounds could reflect tissue-specific changes in the oxidative state of sGC and might help direct the clinical development of these novel classes of therapeutic agents. ER -