Cardioprotective effects of pinacidil pretreatment and lazaroid (U74500A) preservation in isolated rat hearts after 12-hour hypothermic storage.
BACKGROUND
Two important processes in the preservation of the function of donor hearts are the maintenance of ATP-sensitive potassium channel activity during myocardial ischemia and the scavenging of reactive oxygen species formed during reperfusion. The aim of this study was to compare the effect of three protocols on the preservation of hemodynamic function in isolated rat hearts after hypothermic storage. These protocols were: (1) pretreatment of the heart with a potassium channel opener (200 microM pinacidil); (2) storage of the heart in an aspartate-enriched extracellular cardioplegic solution containing the lazaroid antioxidant, U74500A (30 microM); and (3) a combination of protocols 1 and 2.


METHODS
Hearts from Wistar rats were perfused on a Langendorff apparatus. After stabilization in working mode, baseline measurements of heart rate, coronary and aortic flow, and cardiac output were performed. Hearts (n=6 in each group) were then randomized to protocols 1-3, untreated controls, or vehicle-treated controls. Hearts were stored in extracellular-based preservation solution for 12 hr at 2-3 degrees C, remounted on the perfusion apparatus, and stabilized as before; hemodynamic measurements were then repeated.


RESULTS
Recovery of hemodynamic function was enhanced by pinacidil pretreatment or incorporation of lazaroid in the storage solution, but the combination of these two treatments produced the best results.


CONCLUSIONS
Combined pharmacological activation of ATP-sensitive potassium channels before cardioplegia and the addition of U74500A to the preservation solution is associated with significantly enhanced hemodynamic function in the isolated rat heart after 12 hr of hypothermic storage. These data suggest a novel use for these agents in the transplantation context.
Division of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Darlinghurst NSW, Australia.
Z Y
ZY
Du
M
M
Hicks
P
P
Spratt
J A
JA
Mundy
P S
PS
Macdonald
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003080:Cold Temperature; D006146:Guanidines / Q000494:pharmacology*; D016027:Heart Transplantation; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009926:Organ Preservation; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000975:Antioxidants; D006146:Guanidines; D015221:Potassium Channels; D011281:Pregnatrienes; D020110:Pinacidil; C053356:U 74500A