Original Research ARTICLE
Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress
- 1Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area Unit, GlaxoSmithKline, King of Prussia, PA, USA
- 2Lipid Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area Unit, GlaxoSmithKline, Les Ulis, France
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.
Keywords: soluble guanylate cyclase, cGMP, BAY 60-4552, GSK2181236A, VASP, SHR-SP
Citation: Costell MH, Ancellin N, Bernard RE, Zhao S, Upson JJ, Morgan LA, Maniscalco K, Olzinski AR, Ballard VLT, Herry K, Grondin P, Dodic N, Mirguet O, Bouillot A, Gellibert F, Coatney RW, Lepore JJ, Jucker BM, Jolivette LJ, Willette RN, Schnackenberg CG and Behm DJ (2012) Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress. Front. Pharmacol. 3:128. doi: 10.3389/fphar.2012.00128
Received: 27 April 2012; Paper pending published: 17 May 2012;
Accepted: 18 June 2012; Published online: 05 July 2012.
Edited by:Douglas G. Johns, Merck & Co., USA
Reviewed by:Brett Mitchell, Texas A&M Health Science Center, USA
David McLaren, Merck & Co. Inc., USA
Copyright: © 2012 Costell, Ancellin, Bernard, Zhao, Upson, Morgan, Maniscalco, Olzinski, Ballard, Herry, Grondin, Dodic, Mirguet, Bouillot, Gellibert, Coatney, Lepore, Jucker, Jolivette, Willette, Schnackenberg and Behm. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: David J. Behm, Heart Failure Discovery Performance Unit (UW2523), Metabolic Pathways and Cardiovascular Therapy Area Unit, GlaxoSmithKline, PO Box 1539, 709 Swedeland Road, King of Prussia, PA 19406-0939, USA. e-mail: firstname.lastname@example.org
†Current address: Francoise Gellibert, Medicinal Chemistry Division, Institut de Recherches Servier, rue des Moulineaux, Suresnes, France.