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

Radovits

Szabó

2017

British J Pharmacology

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Phosphodiesterase type 5 (PDE5) selectively hydrolyses the second messenger cGMP into 5 0 -GMP, thereby regulating its intracellular concentrations. Dysregulation of the cGMP-dependent pathway plays a significant role in various cardiovascular diseases. Therefore, its modulation by drugs, such as PDE5 inhibitors, may represent an effective therapeutic approach. There are currently four PDE5 inhibitors available for the treatment of erectile dysfunction: sildenafil, vardenafil, tadalafil and avanafil. Sildenafil and tadalafil have also received Food and Drug Administration approval for the treatment of pulmonary arterial hypertension. This review summarizes the pharmacological aspects and clinical potential of PDE5 inhibition for the treatment of myocardial ischaemia/reperfusion injury and heart failure.This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc Abbreviations Bcl 2, B-cell lymphoma 2; HF, heart failure; IR, ischemia/reperfusion; KCa, calcium-activated potassium channel; LAD, left anterior descending artery; PGC-1α, PPAR gamma coactivator 1-alpha; SIRT1, sirtuin 1 LINKED ARTICLES

Section: Global Myocardial Ischaemia/reperfusion Injurymentioning

confidence: 88%

Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure

Radovits

Szabó

2017

British J Pharmacology

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“…The experimental model was described elsewhere (18)(19)(20). The experimental model was described elsewhere (18)(19)(20).…”

Section: Model Of Heterotopic Heart Transplantationmentioning

confidence: 99%

“…Based on published in vitro and in vivo findings, we hypothesized that the treatment of BDD with NOD improves both donor and graft left-ventricular (LV) function in our well-established rat model of heterotopic heart transplantation (18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Donor Preconditioning After the Onset of Brain Death With Dopamine Derivate n-Octanoyl Dopamine Improves Early Posttransplant Graft Function in the Rat

American Journal of Transplantation

Radovits

et al. 2017

Heart transplantation is the therapy of choice for end-stage heart failure. However, hemodynamic instability, which has been demonstrated in brain-dead donors (BDD), could also affect the posttransplant graft function. We tested the hypothesis that treatment of the BDD with the dopamine derivate n-octanoyl-dopamine (NOD) improves donor cardiac and graft function after transplantation. Donor rats were given a continuous intravenous infusion of either NOD (0.882 mg/kg/h, BDD+NOD, n = 6) or a physiological saline vehicle (BDD, n = 9) for 5 h after the induction of brain death by inflation of a subdural balloon catheter. Controls were sham-operated (n = 9). In BDD, decreased left-ventricular contractility (ejection fraction; maximum rate of rise of left-ventricular pressure; preload recruitable stroke work), relaxation (maximum rate of fall of left-ventricular pressure; Tau), and increased end-diastolic stiffness were significantly improved after the NOD treatment. Following the transplantation, the NOD-treatment of BDD improved impaired systolic function and ventricular relaxation. Additionally, after transplantation increased interleukin-6, tumor necrosis factor TNF-α, NF-kappaB-p65, and nuclear factor (NF)-kappaB-p105 gene expression, and increased caspase-3, TNF-α and NF-kappaB protein expression could be significantly downregulated by the NOD treatment compared to BDD. BDD postconditioning with NOD through downregulation of the pro-apoptotic factor caspase-3, pro-inflammatory cytokines, and NF-kappaB may protect the heart against the myocardial injuries associated with brain death and ischemia/reperfusion.

“…The transplantations were performed in an isogenic Lewis to Lewis rat strain using the experimental model previously described (Loganathan et al, 2015). Briefly, the donor rats were anaesthetized with a single i.p.…”

mentioning

confidence: 99%

“…Myocardial gene expression of Bax, caspase-12, caspase-3, catalase, c-Jun, glutathione peroxidase (GPX)-4, NADPH oxidase (NOX)-2, NOX-4 and SOD-1 were performed by quantitative PCR (qPCR), as described (Loganathan et al, 2015). Sample quantifications were normalized to GAPDH expression.…”

mentioning

confidence: 99%

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

Szczesny

Marcatti

et al. 2017

British J Pharmacology

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*Equally contributed. BACKGROUND AND PURPOSEOlaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) are approved as anti-cancer drugs in humans. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effects of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in vivo model of cardiac transplantation. EXPERIMENTAL APPROACHH9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10μM) were challenged with either hydrogen peroxide (H 2 O 2 ) or with glucose oxidase (GOx, which generates H 2 O 2 in the tissue culture medium). Cell viability assays (MTT, lactate dehydrogenase) and Western blotting for PARP and its product, PAR was performed. Heterotopic heart transplantation was performed in Lewis rats; recipients were treated either with vehicle or olaparib (10 mg kg -1 ). Left ventricular function of transplanted hearts was monitored via a Millar catheter. Multiple gene expression in the graft was measured by qPCR. KEY RESULTSOlaparib blocked autoPARylation of PARP1 and attenuated the rapid onset of death in H9c2 cells, induced by H 2 O 2 , but did not affect cell death following chronic, prolonged oxidative stress induced by GOx. In rats, after transplantation, left ventricular systolic and diastolic function were improved by olaparib. In the transplanted hearts, olaparib also reduced gene expression for c-jun, caspase-12, catalase, and NADPH oxidase-2. CONCLUSIONS AND IMPLICATIONSOlaparib protected cardiomyocytes against oxidative stress and improved graft contractility in a rat model of heart transplantation. These findings raise the possibility of repurposing this clinically approved oncology drug, to be used in heart transplantation. LINKED ARTICLES