Functional recovery after dantrolene-supplementation of cold stored hearts using an ex vivo isolated working rat heart model

Abstract

The ryanodine receptor antagonist dantrolene inhibits calcium release from the sarcoplasmic reticulum and reduces cardiac ischaemia-reperfusion injury (IRI) in global warm ischaemia models however the cardioprotective potential of dantrolene under hypothermic conditions is unknown. This study addresses whether the addition of dantrolene during cardioplegia and hypothermic storage of the donor heart can improve functional recovery and reduce IRI. Using an ex vivo isolated working heart model, Wistar rat (3 month and 12 month) hearts were perfused to acquire baseline haemodynamic measurements of aortic flow, coronary flow, cardiac output, pulse pressure and heart rate. Hearts were arrested and stored in Celsior preservation solution supplemented with 0.2–40 μM dantrolene for 6 hours at 4°C, then reperfused (15 min Langendorff, 30 min working mode). In 3-month hearts, supplementation with 1 μM dantrolene significantly improved aortic flow and cardiac output compared to unsupplemented controls however lactate dehydrogenase (LDH) release and contraction bands were comparable. In contrast, 40 μM dantrolene-supplementation yielded poor cardiac recovery, increased post-reperfusion LDH but reduced contraction bands. All 3-month hearts stored in dantrolene displayed significantly reduced cleaved-caspase 3 intensities compared to controls. Analysis of cardioprotective signalling pathways showed no changes in AMPKα however dantrolene increased STAT3 and ERK1/2 signaling in a manner unrelated to functional recovery and AKT activity was reduced in 1 μM dantrolene-stored hearts. In contrast to 3-month hearts, no significant improvements were observed in the functional recovery of 12-month hearts following prolonged storage in 1 μM dantrolene. Conclusions: Dantrolene supplementation at 1 μM during hypothermic heart preservation improved functional recovery of young, but not older (12 month) hearts. Although the molecular mechanisms responsible for dantrolene-mediated cardioprotection are unclear, our studies show no correlation between improved functional recovery and SAFE and RISK pathway activation.

Oxidative Stress-Responsive MicroRNAs in Heart Injury

“…This leads to graft dysfunction, like allograft rejection, delayed graft function, or primary nonfunction, as well as to endothelial and parenchymal cell injury [52,53]. To increase success of the heart transplantation, experimental studies have focused on the enrichment of antioxidative substrates in cardioplegia solution and pump prime solution [54][55][56][57][58][59], suggesting the importance of continuous research into antioxidants.…”

Exercise Preconditioning Preserves Cardiac Function and Enhances Cardiac Recovery Following Dobutamine Stimulation in Doxorubicin-Treated Rat Hearts

“…Overall, nonpaced HR values were lower than normal physiological resting HR values in rats, which is a typical observation in this model. [69][70][71] In the absence of neural stimulation and circulating catecholamines, RPP may not be as indicative of myocardial stress. In the isolated Langendorff preparation, RPP is not associated with myocardial oxygen consumption, but it is unclear whether this also applies to the working heart model.…”

Intestinal Ischemia-Reperfusion Injury and Calcium Channel Blockers: Getting to the Core of the Problem

“…The site of action of dantrolene is the sarcoplasmic reticulum ryanodine receptor Ca 2þ channel, where it inhibits the depolarization-induced release of Ca 2þ from the sarcoplasmic reticulum into the cytoplasm, interfering with excitation-contraction coupling. Dantrolene has been found to reduce spontaneous Ca 2þ release from the sarcoplasmic reticulum of heart failure-derived cardiomyocytes [5] and improve the functional recovery of young hearts following hypothermic heart preservation when using dantrolene-supplemented preservation solution [6]. Common side effects of dantrolene administration are drowsiness, headaches, anorexia, diarrhea, nausea and vomiting [1].…”