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  • br Conclusion The following is the supplementary data relate

    2021-11-22


    Conclusion The following is the supplementary data related to this article.
    Conflict of interest
    Author contributions
    Heart transplantation is the most important treatment for end-stage heart failure. Ischemia/reperfusion injury is a common condition during transplantation surgery and is recognized as a major determinant of primary graft dysfunction. During reperfusion, the acute ischemic myocardium is subjected to several abrupt biochemical and metabolic changes, including generation of reactive oxygen species, intracellular calcium overload, 6,7-dihydroxy Bergamottin synthesis depletion, and acidosis. In the cardiovascular system, the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway plays an important role as it controls vasodilation through smooth muscle relaxation, inhibits platelet aggregation, and prevents vascular smooth muscle proliferation. The physiologic activation of the sGC on binding of NO to its heme moiety results in conversion of guanosine triphosphate to cGMP. Under pathologic conditions, the NO/sGC/cGMP pathway deteriorates, and its modulation by clinically relevant therapeutic modalities such as sGC activators and phosphodiesterase-5 inhibitors has become a promising strategy. Concurrent evidence has shown that cGMP and its downstream target protein kinase G play a crucial role in survival signaling of pre-conditioning and post-conditioning. We and others demonstrated that pharmacologic pre-conditioning with inhibitors of phosphodiesterase-5, an enzyme that catalyzes the breakdown of cGMP, augments myocardial protection in heart transplantation in rats., Because NO-mediated cGMP synthesis requires sGC, impaired sGC activity may contribute to reduced and/or poor responsiveness to endogenous NO. However, current therapies using organic nitrates that activate sGC after bioconversion to NO develop tolerance when used as sustained therapy. Their efficacy is limited by the absence of clinically relevant anti-platelet activity and the inability to activate NO-insensitive sGC. Also, the use of organic nitrates under oxidative conditions promotes peroxynitrite formation, which can prevent its therapeutic effect. As an alternative therapeutic approach, a novel class of drugs that modulate the sGC/cGMP signal transduction pathway has been developed. In pre-clinical studies, the sGC activator cinaciguat (BAY 58-2667) was shown to activate the oxidized (Fe)/heme-free forms of sGC and to preferentially dilate the diseased vs non-diseased vasculature. The use of cinaciguat in experimental models of disease has been investigated. We and Krieg et al demonstrated a potential role for cinaciguat as a pharmacologic agent for the prevention and treatment of experimentally induced ischemic heart injury., A role of cinaciguat in the treatment of chronic renal disease progression was also examined. Moreover, activation of sGC was shown to reverse experimental pulmonary hypertension in a mouse model. Although the activation of the impaired NO/cGMP/protein kinase G pathway seems to be an important mechanism in cardiac protection during heart transplantation, the effect of targeting the NO-unresponsive sGC has not been investigated. Because of the lack of sufficient pharmacologic approaches to reduce ischemia/reperfusion injury in cardiac surgery and especially in heart transplantation, which is mainly limited by the ischemic time of the graft, we assessed the efficacy of cinaciguat-related cardioprotection in our well-established rat, model of heterotopic heart transplantation. Methods
    Results
    Discussion Despite the improvements in medical and device therapies for the treatment of heart failure, the proportion of end-stage heart failure patient continues to increase and the heart transplantation remains the gold standard therapeutic option. Because of long ischemic times, primary graft dysfunction is the most frequent complication in the immediate post-operative period after cardiac transplantation. Fast recovery of myocardial function is essential for the success of cardiac transplantation. Based on this knowledge, we focused our investigations on the effects of cinaciguat in the early phase of reperfusion after heart transplantation. During reperfusion, on one hand, improved coronary perfusion is required to reestablish the supply of substrates and especially of oxygen. On the other hand, vasodilation is impaired as a result of endothelial dysfunction. Additionally, superoxide production during reperfusion scavenges the small amount of remaining NO and stops a sufficient blood and substrate supply to myocardial tissue. Our results indicate that cinaciguat breaks this vicious cycle by affecting this pathway 1 step downstream and reactivating oxidized sGC.