Effects of soluble guanylate cyclase activation on heart transplantation in a rat model.

Abstract

BACKGROUND:

The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is an important key mechanism to protect the heart from ischemia/reperfusion injury. However, this pathway is disrupted in several cardiovascular diseases as a result of decreased NO bioavailability and increased NO-insensitive forms of sGC. Cinaciguat preferentially activates these NO-insensitive, oxidized forms of sGC.

METHODS:

We assessed the hypothesis that targeting NO-unresponsive sGC would protect the graft against ischemia/reperfusion injury in a rat heart transplantation model. Before explantation, donor Lewis rats received methylcellulose (1%) vehicle or cinaciguat 10 mg/kg. The hearts were excised, stored in cold preservation solution, and heterotopically transplanted. We evaluated in vivo left ventricular function of the graft.

RESULTS:

After transplantation, decreased left ventricular systolic pressure (77 ± 3 mm Hg vs 123 ± 13 mm Hg, p < 0.05), dP/dt(max) (1,703 ± 162 mm Hg vs 3,350 ± 444 mm Hg, p < 0.05), and dP/dt(min) (995 ± 110 mm Hg vs 1,925 ± 332 mm Hg, p < 0.05) were significantly increased by cinaciguat. Coronary blood flow was significantly higher in the cinaciguat group compared with the control group. Additionally, cinaciguat increased adenosine triphosphate levels (1.9 ± 0.4 µmol/g vs 6.6 ± 0.8 µmol/g, p < 0.05) and improved energy charge potential. After transplantation, increased c-jun messenger RNA expression was downregulated, whereas superoxide dismutase-1 and cytochrome-c oxidase mRNA levels were upregulated by cinaciguat. Cinaciguat also significantly decreased myocardial DNA strand breaks induced by ischemia/reperfusion during transplantation and reduced death of cardiomyocytes in a cellular model of oxidative stress.

CONCLUSIONS:

By interacting with NO-unresponsive sGC, cinaciguat enhances the protective effects of the NO/cGMP pathway at different steps of signal transduction after global myocardial ischemia/reperfusion. Its clinical use as pre-conditioning agent could be a novel approach in cardiac surgery.

• Authors: Sivakkanan Loganathan, Sevil Korkmaz-Icöz, Tamás Radovits, Shiliang Li, Beatrice Mikles, Enikő Barnucz, Kristóf Hirschberg, Matthias Karck, Gábor Szabó
• Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation (J Heart Lung Transplant) Vol. 34 Issue 10 Pg. 1346-53 (Oct 2015) ISSN: 1557-3117 [Electronic] United States
• PMID: 26210750 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Benzoates
• Receptors, Cytoplasmic and Nuclear
• BAY 58-2667
• Guanylate Cyclase
• Soluble Guanylyl Cyclase

Topics

• Animals
• Benzoates (therapeutic use)
• Enzyme Activation
• Guanylate Cyclase (physiology)
• Heart Transplantation (adverse effects)
• Male
• Myocardial Reperfusion Injury (etiology, prevention & control)
• Rats
• Rats, Inbred Lew
• Receptors, Cytoplasmic and Nuclear (physiology)
• Soluble Guanylyl Cyclase
• Transplantation Conditioning
• Ventricular Function, Left