Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress. |
| Authors: |
Costell, Melissa H Ancellin, Nicolas Bernard, Roberta E Zhao, Shufang Upson, John J Morgan, Lisa A Maniscalco, Kristeen Olzinski, Alan R Ballard, Victoria L T Herry, Kenny Grondin, Pascal Dodic, Nerina Mirguet, Olivier Bouillot, Anne Gellibert, Francoise Coatney, Robert W Lepore, John J Jucker, Beat M Jolivette, Larry J Willette, Robert N Schnackenberg, Christine G Behm, David J
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| Citation: |
Costell MH, etal., Front Pharmacol. 2012 Jul 5;3:128. doi: 10.3389/fphar.2012.00128. eCollection 2012. |
| RGD ID: |
25824851 |
| Pubmed: |
PMID:22783192 (View Abstract at PubMed) |
| PMCID: |
PMC3389674 (View Article at PubMed Central) |
| DOI: |
DOI:10.3389/fphar.2012.00128 (Journal Full-text) |
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.
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