Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress

被引：48

作者：

Costell, Melissa H. ^{[1
]}

Ancellin, Nicolas ^{[2
]}

Bernard, Roberta E. ^{[1
]}

Zhao, Shufang ^{[1
]}

Upson, John J. ^{[1
]}

Morgan, Lisa A. ^{[1
]}

Maniscalco, Kristeen ^{[1
]}

Olzinski, Alan R. ^{[1
]}

Ballard, Victoria L. T. ^{[1
]}

Herry, Kenny ^{[2
]}

Grondin, Pascal ^{[2
]}

Dodic, Nerina ^{[2
]}

Mirguet, Olivier ^{[2
]}

Bouillot, Anne ^{[2
]}

Gellibert, Francoise ^{[2
]}

Coatney, Robert W. ^{[1
]}

Lepore, John J. ^{[1
]}

Jucker, Beat M. ^{[1
]}

Jolivette, Larry J. ^{[1
]}

Willette, Robert N. ^{[1
]}

Schnackenberg, Christine G. ^{[1
]}

Behm, David J. ^{[1
]}

机构：

[1] GlaxoSmithKline, Metab Pathways & Cardiovasc Therapy Area Unit, Heart Failure Discovery Performance Unit, King Of Prussia, PA 19406 USA

[2] GlaxoSmithKline, Metab Pathways & Cardiovasc Therapy Area Unit, Lipid Metab Discovery Performance Unit, Les Ulis, France

来源：

FRONTIERS IN PHARMACOLOGY | 2012年 / 3卷

关键词：

soluble guanylate cyclase; cGMP; BAY; 60-4552; GSK2181236A; VASP; SHR-SP; NITRIC-OXIDE; ENDOTHELIAL DYSFUNCTION; CARDIAC-HYPERTROPHY; PROTEIN-KINASE; MYOCARDIAL-ISCHEMIA; ORGAN DAMAGE; HEART; HYPERTENSION; INHIBITORS; MORTALITY;

D O I：

10.3389/fphar.2012.00128

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 G5K2181236A [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 G5K2181236A, decreased urine output, and improved survival. Conversely, the low dose of G5K2181236A, 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 G5K2181236A. 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 G5K2181236A 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, G5K2181236A 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.

引用

页数：14

共 36 条

[1] Eprosartan reduces cardiac hypertrophy, protects heart and kidney, and prevents early mortality in severely hypertensive stroke-prone rats [J].