PhD Scientific Days 2018

Budapest, April 19–20, 2018

Pharmacological stimulation of the NO/SGC/cGMP pathway reduces ischemia-reperfusion injury and improves donor organ function in a rat model of heterotopic heart transplantation

Németh, Balázs

1 Balázs Tamás Németh, Heart and Vascular Center, Semmelweis University, Budapest
2 Kálmán Benke, Heart and Vascular Center, Semmelweis University, Budapest
3 Alex Ali Sayour, Heart and Vascular Center, Semmelweis University, Budapest
4 Bence Károly Ágg, Heart and Vascular Center, Semmelweis University, Budapest
5 Attila Oláh, Heart and Vascular Center, Semmelweis University, Budapest
6 Mihály Ruppert, Heart and Vascular Center, Semmelweis University, Budapest
7 Klára Stark, Heart and Vascular Center, Semmelweis University, Budapest
8 Miklós Pólos, Heart and Vascular Center, Semmelweis University, Budapest
9 István Hartyánszky, Heart and Vascular Center, Semmelweis University, Budapest
10 Béla Merkely, Heart and Vascular Center, Semmelweis University, Budapest
11 Zoltán Szabolcs, Heart and Vascular Center, Semmelweis University, Budapest
12 Tamás Radovits, Heart and Vascular Center, Semmelweis University, Budapest

Language of the presentation

Hungarian

Text of the abstract

Introduction: Heart transplantation (HTX) is the definitive therapy of end-stage heart failure. Ischemia-reperfusion (I/R) injury occurring during transplantation is a primary determinant of long-term outcome of HTX and primary graft insufficiency. The most important pathobiochemical changes induced by reperfusion in the myocardium of the donor organ are increased production of reactive oxygen species (ROS), intracellular Ca2+ overload, energy deficit and acidosis. Modification of the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathway by the sGC stimulator riociguat appears to be a promising new pharmacological option. We aimed at characterizing the cardio-protective effects of this drug in a rat model of heterotopic heart transplantation.
Methods: Donor Lewis rats were treated orally with either riociguat (10mg/BWkg) or placebo for two days. Hearts were stored for an hour in cold preservation solution (Custodiol) following explantation, then were transplanted heterotopically. One hour after initiation of reperfusion, left ventricular (LV) pressure-volume relations and coronary flow were recorded in order to assess post-transplant graft function. Molecular biological measurements and histological examination were also completed.
Results: LV contractility (LV systolic pressure at 120µl of LV volume: 117±13 vs. 48±5mmHg, p<0.001; dP/dtmax: 2963±221 vs. 1653±159mmHg/s, p<0.001) and active relaxation (dP/dtmin at 120µl of LV volume: -2014±305 vs. -1063±177mmHg/s, p=0.019) improved significantly after an hour of reperfusion, while alteration of coronary flow standardized to heart weight (2.52±0.34 vs. 1.67±0.22ml/min/g, p=0.06) was a trend following pretreatment with riociguat. Myocardial expression of antioxidant markers were significantly improved after heart transplantation.
Conclusions: Pharmacological preconditioning with riociguat decreases I/R injury and improves donor organ function in our small animal model of heart transplantation. The observed cardio-protective effect might be attributed to the stimulated sGC and increased myocardial cGMP-signaling. Riociguat therefore might be a potential cardio-protective agent in the inventory of heart transplantation surgery and during cardiac surgical procedures requiring sustained ischemia.

Data of the presenter

Doctoral School: Basic Medicine
Program: Cardiovascular Disorders, Physiology and Medicine of Ischaemic Circulatory Diseases
Supervisor: Tamás Radovits
E-mail address: nemethbl@gmail.com