A novel bisindolylmaleimide derivative enhances functional recovery of heart after long-term hypothermic heart preservation.
BACKGROUND
Functional recovery following heart transplantation mainly depends on the ability of preservative solution in providing the physical and biochemical environment so as to maintain the viability of the tissue during preservation and in reperfusion. Here we demonstrate the protective effects of a novel bisindolylmaleimide derivative, MS1, on enhancing the functional recovery of the heart following long-term hypothermic preservation when added to the preservative solution.


METHODS
After anesthesia and artificial ventilation, the hearts were rapidly isolated and perfused with Kreb's Henseleit buffer at 37 degrees C in working mode. After 30 minutes of perfusion, the hearts were arrested with cardioplegic solution and preserved in University of Wisconsin solution with (UW-MS1 group) or without MS1 (UW-Vehicle group) for 12 h at 4 degrees C. After 12 hours, the hearts were reperfused for 60 minutes.


RESULTS
MS1 treated hearts showed: a) significant recovery of cardiac functions (P<0.001), b) well-preserved myocardial ATP levels (P<0.001), c) less myocardial water content (P<0.01), d) reduced oxidative stress (P<0.001), e) less intracellular swelling and well-preserved mitochondria, and g) activation of cell survival cascades compared to the control hearts preserved in UW solution without MS1. In contrast, these protective effects of MS1 were abolished on opening the permeability transition pore before MS1 treatment.


CONCLUSIONS
These results altogether indicate the efficacy of this compound in protecting the myocardium against reperfusion injury and thus making this drug a clinically useful tool in patients undergoing reperfusion after cardiac surgeries.
Katare
Rajesh Gopalrao
RG
Department of Thoracic & Cardiovascular Surgery, Kochi Medical School, Nankoku, Kochi, Japan.
Zhitian
Zou
Z
Sodeoka
Mikiko
M
Sasaguri
Shiro
S
D000241:Adenosine; D000493:Allopurinol; D000818:Animals; D005978:Glutathione; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007035:Hypothermia; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011887:Raffinose; D051381:Rats; D017208:Rats, Wistar
D007211:Indoles; D007328:Insulin; D008301:Maleimides; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D011493:Protein Kinase C; D005978:Glutathione; D000241:Adenosine; C088060:bisindolylmaleimide; D011887:Raffinose