Zoniporide preserves left ventricular compliance during ventricular fibrillation and minimizes postresuscitation myocardial dysfunction through benefits on energy metabolism.
OBJECTIVE
To investigate whether sodium-hydrogen exchanger isoform-1 (NHE-1) inhibition attenuates myocardial injury during resuscitation from ventricular fibrillation through effects on energy metabolism, using an open-chest pig model in which coronary perfusion was controlled by extracorporeal circulation.


METHODS
Randomized controlled animal study.


METHODS
University research laboratory.


METHODS
Male domestic pigs.


METHODS
Ventricular fibrillation was electrically induced and left untreated for 8 mins, after which extracorporeal circulation was started and its flow adjusted to maintain a coronary perfusion pressure of 10 mm Hg. After 10 mins of extracorporeal circulation, restoration of spontaneous circulation was attempted by epicardial defibrillation and gradual reduction in extracorporeal flow. Two groups of eight pigs each were randomized to receive the NHE-1 inhibitor zoniporide (3 mg.kg-1) or vehicle control immediately before starting extracorporeal circulation.


RESULTS
Identical extracorporeal flows (approximately = 9% of baseline cardiac index) were required in zoniporide and control groups to attain the target coronary perfusion pressure, resulting in comparable left anterior descending coronary artery blood flow (9 +/- 1 and 10 +/- 1 mL.min-1) and resistance (0.10 +/- 0.01 and 0.10 +/- 0.01 dyne.sec.cm(-5)). Yet zoniporide prevented reductions in left ventricular volume and wall thickening while favoring higher myocardial creatine phosphate to creatine ratios (0.14 +/- 0.03 vs. 0.06 +/- 0.01, p < .05), lower myocardial adenosine (0.7 +/- 0.1 vs. 1.3 +/- 0.2, p < .05), and lower myocardial lactate (80 +/- 9 vs. 125 +/- 6 mmol.kg-1, p < .001). Postresuscitation, zoniporide-treated pigs had higher left ventricular ejection fraction (0.57 +/- 0.07 vs. 0.29 +/- 0.05, p < .05) and higher cardiac index (4.8 +/- 0.4 vs. 3.4 +/- 0.2 L.min-1.m-2, p < .05).


CONCLUSIONS
Zoniporide ameliorated myocardial injury during resuscitation from ventricular fibrillation through beneficial effects on energy metabolism without effects on coronary vascular resistance and coronary blood flow.
Ayoub
Iyad M
IM
Department of Medicine, Rosalind Franklin University of Medicine and Science, and North Chicago VA Medical Center, North Chicago, IL, USA.
Kolarova
Julieta D
JD
Kantola
Ronald L
RL
Radhakrishnan
Jeejabai
J
Wang
Sufen
S
Gazmuri
Raúl J
RJ
D000818:Animals; D004734:Energy Metabolism; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*
D006146:Guanidines; D011720:Pyrazoles; C424422:zoniporide