HOE-642 (cariporide) alters pH(i) and diastolic function after ischemia during reperfusion in pig hearts in situ.
The specific Na(+)/H(+) exchange inhibitor HOE-642 prevents ischemic and reperfusion injury in the myocardium. Although this inhibitor alters H(+) ion flux during reperfusion in vitro, this action has not been confirmed during complex conditions in situ. Myocardial intracellular pH (pH(i)) and high-energy phosphates were monitored using (31)P magnetic resonance spectroscopy in open-chest pigs supported by cardiopulmonary bypass during 10 min of ischemia and reperfusion. Intravenous HOE-642 (2 mg/kg; n = 8) administered before ischemia prevented the increases in diastolic stiffness noted in control pigs (n = 8), although it did not alter the postischemic peak-elastance or pressure-rate product measured using a distensible balloon within the left ventricle. HOE-642 induced no change in pH(i) during ischemia but caused significant delays in intracellular realkalinization during reperfusion. HOE-642 did not alter phosphocreatine depletion and repletion but did improve ATP preservation. Na(+)/H(+) exchange inhibition through HOE-642 delays intracellular alkalinization in the myocardium in situ during reperfusion in association with improved diastolic function and high-energy phosphate preservation.
Portman
M A
MA
Division of Cardiology, Department of Pediatrics, University of Washington and Children's Hospital and Regional Medical Center, Seattle, Washington 98105, USA. mportm@chmc.org
Panos
A L
AL
Xiao
Y
Y
Anderson
D L
DL
Ning
X
X
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003971:Diastole / Q000187:drug effects* / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology*; D011522:Protons; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology*; D013552:Swine
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D011522:Protons; D013450:Sulfones; C093373:cariporide; D000255:Adenosine Triphosphate