Zoniporide preserves left ventricular compliance during ventricular fibrillation and minimizes postresuscitation myocardial dysfunction through benefits on energy metabolism.

Abstract

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.

DESIGN:

Randomized controlled animal study.

SETTING:

University research laboratory.

SUBJECTS:

Male domestic pigs.

INTERVENTIONS:

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.

MEASUREMENTS AND MAIN 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.

• Authors: Iyad M Ayoub, Julieta D Kolarova, Ronald L Kantola, Jeejabai Radhakrishnan, Sufen Wang, Raúl J Gazmuri
• Journal: Critical care medicine (Crit Care Med) Vol. 35 Issue 10 Pg. 2329-36 (Oct 2007) ISSN: 0090-3493 [Print] United States
• PMID: 17944021 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: (C) 2007 Lippincott Williams & Wilkins, Inc.

Chemical References

• Guanidines
• Pyrazoles
• zoniporide

Topics

• Animals
• Energy Metabolism
• Guanidines (pharmacology, therapeutic use)
• Heart (drug effects, physiopathology)
• Male
• Myocardium (metabolism)
• Pyrazoles (pharmacology, therapeutic use)
• Swine
• Ventricular Fibrillation (drug therapy, metabolism, physiopathology)
• Ventricular Function, Left (drug effects)