A new concept of long-term donor heart preservation: nucleoside transport inhibition.
Myocardial ischemia results in a breakdown of adenosine triphosphate (ATP), which is associated with an accumulation of its catabolites adenosine and inosine. Adenosine is a potent but ineffective cardioprotective agent because it is rapidly transported to the endothelium and irreversibly catabolized. With the use of specific nucleoside transport inhibition (NTI), however, endogenous adenosine may accumulate at its site of production, and its further breakdown and washout on reperfusion is prevented. In this study we tested this concept and assessed the effect of NTI drug administration on 24 hours' preservation of donor hearts for transplantation. Twelve dogs were randomly allocated to two groups. In the first group (group 1, n = 6) the hearts were arrested with a cold hyperkalemic cardioplegic solution, excised and stored for 24 hours at 0.5 degrees C. After 24 hours the hearts were transplanted orthotopically. In group 2 (n = 6) the same procedure was followed, but a specific NTI agent was added to the cardioplegic solution (1 mg/L) and administered intravenously to the recipient dog before reperfusion of the transplanted heart (0.1 mg/kg). Despite maximal positive inotropic support, none of the control animals (group 1) could be weaned from cardiopulmonary bypass: within 1 hour irreversible cardiogenic shock occurred in all animals. In group 2 all hearts could be weaned from cardiopulmonary bypass and were hemodynamically stable without positive inotropic support. Serial transmural left ventricular biopsies revealed in group 1 moderate catabolism of ATP during cold storage. On reperfusion a further decline of the ATP content was seen, and the accumulated nucleosides were washed out.(ABSTRACT TRUNCATED AT 250 WORDS)
Flameng
W
W
Department of Cardiac Surgery, Katholieke Universiteit Leuven, Belgium.
Sukehiro
S
S
Möllhoff
T
T
Van Belle
H
H
Janssen
P
P
D000241:Adenosine / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002314:Cardioplegic Solutions; D004285:Dogs; D006321:Heart; D016027:Heart Transplantation / Q000502:physiology; D006439:Hemodynamics / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D009926:Organ Preservation / Q000379:methods*; D010879:Piperazines / Q000494:pharmacology*; D013997:Time Factors
D002314:Cardioplegic Solutions; D010879:Piperazines; C072040:draflazine; D000255:Adenosine Triphosphate; D000241:Adenosine