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

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• 作者：Sivakkanan Loganathan ; MD^a ; ^b ; ¹ ; ^{sivakkanan@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Sevil Korkmaz-Icö ; z ; PhD^a ; ¹ ; Tamá ; s Radovits ; MD ; PhD^c ; Shiliang Li ; MD^a ; Beatrice Mikles^a ; Enikő Barnucz ; MD^a ; Kristó ; f Hirschberg ; MD ; PhD^a ; Matthias Karck ; MD^a ; Gá ; bor Szabó ; MD ; PhD^a
• 关键词：heart transplantation ; ischemia/reperfusion ; soluble guanylate cyclase ; soluble guanylate cyclase activation ; cinaciguat ; nitric oxide
• 刊名：Journal of Heart and Lung Transplantation
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：34
• 期：10
• 页码：1346-1353
• 全文大小：1728 K

文摘

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.